Device and Implantation System for Electrical Stimulation of Biological Systems

ABSTRACT

The present specification discloses devices and methodologies for the treatment of GERD. Individuals with GERD may be treated by implanting a stimulation device within the patient&#39;s lower esophageal sphincter and applying electrical stimulation to the patient&#39;s lower esophageal sphincter, in accordance with certain predefined protocols. The presently disclosed devices have a simplified design because they do not require sensing systems capable of sensing when a person is engaged in a wet swallow, have improved energy storage requirements, enable improved LES function while concurrently delivering additional health benefits, and enable improved LES function post stimulation termination.

CROSS REFERENCE

The present application is a continuation application of U.S. patentapplication Ser. No. 14/665,226, entitled “Device and ImplantationSystem for Electrical Stimulation of Biological Systems” and filed onMar. 23, 2015, which is a continuation application of U.S. patentapplication Ser. No. 13/463,803, of the same title, filed on May 3,2012, and issued as U.S. Pat. No. 9,020,597 on Apr. 28, 2015, which is acontinuation-in-part application of U.S. patent application Ser. No.13/041,063, of the same title, filed on Mar. 4, 2011, issued on Apr. 29,2014 as U.S. Pat. No. 8,712,529, and assigned to the applicant of thepresent application, which, in turn, relies on U.S. Provisional PatentApplication Nos. 61/310,755, filed on Mar. 5, 2010, 61/318,843, filed onMar. 30, 2010, 61/328,702, filed on Apr. 28, 2010, 61/371,146, filed onAug. 5, 2010, 61/384,105, filed on Sep. 17, 2010, 61/414,378, filed onNov. 16, 2010, 61/422,967, filed on Dec. 14, 2010, and 61/444,849, filedon Feb. 21, 2011, all of the same title, for priority.

U.S. patent application Ser. No. 13/463,803 is also acontinuation-in-part application of U.S. patent application Ser. No.13/419,255, entitled “Systems and Methods for Electrically Stimulatingthe Lower Esophageal Sphincter to Treat Gastroesophageal RefluxDisease”, filed on Mar. 13, 2012, issued on Sep. 17, 2013 as U.S. Pat.No. 8,538,534, and assigned to the applicant of the present application,which, in turn, is a continuation application of U.S. patent applicationSer. No. 12/300,614, entitled “Use of Electrical Stimulation of theLower Esophageal Sphincter to Modulate Lower Esophageal SphincterPressure”, filed on Nov. 12, 2008, and issued on Apr. 17, 2012 as U.S.Pat. No. 8,160,709, which is a national stage entry of PCT applicationnumber PCT/US07/68907, entitled “Electrical Stimulation of the LowerEsophageal Sphincter” and filed on May 14, 2007, which, in turn, relieson U.S. Provisional Patent Application No. 60/801,452 entitled “Use ofElectrical Stimulation and Neural High Frequency Stimulation to ModulateLower Esophageal Sphincter Pressure” and filed on May 18, 2006, forpriority.

U.S. patent application Ser. No. 13/463,803 also relies on U.S. PatentProvisional Application No. 61/482,145, entitled “Methods of TreatingObesity and Controlling Weight Gain” and filed on May 3, 2011. Each ofthe above applications is hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

This invention relates generally to a method and apparatus forelectrical stimulation of the biological systems. More particularly,this invention relates to a method and apparatus for treatinggastroesophageal reflux disease (GERD) by electrically stimulating aportion of the gastrointestinal system.

BACKGROUND OF THE INVENTION

Gastro-esophageal reflux disease (GERD) is a common problem and isexpensive to manage in both primary and secondary care settings. Thiscondition results from exposure of esophageal mucosa to gastric acid andbile as the gastro-duodenal content refluxes from the stomach into theesophagus. The acid and bile damages the esophageal mucosa resulting inheartburn, ulcers, bleeding, and scarring, and long term complicationssuch as Barrett's esophagus (pre-cancerous esophageal lining) andadeno-cancer of the esophagus. Patients with GERD may only experiencesymptoms during the day, referred to as diurnal GERD, and may notexperience any GERD symptoms at night, referred to as nocturnal GERD.Diurnal or daytime or upright GERD has been associated with tLESR, andmay be diagnosed where a patient has symptoms of heartburn,regurgitation or both.

The severity of GERD increases progressively from postprandial toupright, to supine, to bipositional reflux. A structural defect asreflected by decreased LES pressure and length is also significantlyless common with postprandial and upright reflux. The improvedesophageal sensation associated with improved saliva production thatneutralizes the refluxed acid and increased clearance of the refluxateaided by gravity results in lesser esophageal damage.

Lifestyle advice and antacid therapy are advocated as first linetreatment for the disease. However, since most patients with moderate tosevere cases of diurnal GERD do not respond adequately to thesefirst-line measures and need further treatment, other alternativesincluding pharmacological, endoscopic, and surgical treatments areemployed.

The most commonly employed pharmacological treatment is daily use of H2receptor antagonists (H2RAs) or proton-pump inhibitors (PPIs) for acidsuppression. Since gastro-esophageal reflux disease usually relapsesonce drug therapy is discontinued, most patients with the disease,therefore, need long-term drug therapy. However, daily use of PPIs orH2RAs is not universally effective in the relief of diurnal GERDsymptoms or as maintenance therapy. Additionally, not all patients arecomfortable with the concept of having to take daily or intermittentmedication for the rest of their lives and many are interested innonpharmacological options for managing their reflux disease.

Several endoscopic procedures for the treatment of diurnal GERD havebeen tried. These procedures can be divided into three approaches:endoscopic suturing wherein stitches are inserted in the gastric cardiato plicate and strengthen the lower esophageal sphincter, endoscopicapplication of energy to the lower esophagus, and injection of bulkingagents into the muscle layer of the distal esophagus. These procedures,however, are not without their risks, besides being technicallydemanding and involving a long procedure time. As a result, theseprocedures have largely been discontinued.

Open surgical or laparoscopic fundoplication is also used to correct thecause of the disease. However, surgical procedures are associated withsignificant morbidity and small but not insignificant mortality rates.Moreover, long-term follow-up with patients treated by surgery suggeststhat many patients continue to need acid suppressive medication. Thereis also no convincing evidence that fundoplication reduces the risk ofesophageal adenocarcinoma in the long term.

While electrical stimulation has been suggested for use in the treatmentof diurnal GERD, an effective electrical stimulation system has yet tobe demonstrated. In particular, the prior art teaches that effectiveelectrical stimulation requires active, real-time sensing for apatient's swallow and, based on a sensed swallow, to immediately ceasestimulation. For example, certain prior art approaches require theconstant sensing of certain physiological changes in the esophagus, suchas changes in esophageal pH, to detect acid reflux and/or esophagealmotility and, based on such sensed changes, initiating or terminating anelectrical stimulation to instantaneously close or open the LES,respectively, thereby avoiding an acid reflux episode. Other prior artapproaches require continuous stimulation with sensing for swallow andstopping stimulation to allow for normal swallow to happen. This createsa complex device and has not proven to be feasible or effective inpractice.

Therefore, there is still a need for a safe and effective method oftreatment that can help alleviate symptoms of diurnal GERD in the longterm, without adversely affecting the quality of life of the patients.In particular, there is a need for simple, efficient diurnal GERD deviceand treatment methods that do not inhibit a patient from swallowing anddo not rely on an instantaneous response from the patient's LES to avoidepisodes of acid reflux. There is a need for treatment protocols anddevices which are programmed to implement such protocols, which can beeasily programmed and do not require complex physiologic sensingmechanisms in order to operate effectively and safely. Moreover, thereis not only a need for better devices in stimulation based therapies,but there is also a need for a safe and minimally invasive method andsystem that enables easy and expeditious deployment of such devices atany desired location in the body.

It is further desirable to have a system for the treatment of diurnalGERD which includes a stimulator and an optional sensor adapted to beplaced in a patient's LES tissue.

It is further desirable to have a system for the treatment of diurnalGERD which includes an active implantable medical device (AIMD) andtemporary sensor adapted to be placed in a patient's GI lumen where thesensors are designed to naturally dissolve or pass out through the lumenand the AIMD is adapted to dynamically acquire, process, measure thequality of, and use sensed data only when the sensor is present.

It is further desirable to have a system for the temporary treatment ofdiurnal GERD which includes an AIMD, which is adapted to be placed in apatient's GI lumen, designed to naturally dissolve or pass out throughthe lumen, and is adapted to deliver electrical stimulation to tissue ator in the vicinity of the LES. Such temporary stimulation scheme canadditionally be used for pre-screening of patients likely to benefitfrom permanent stimulation.

It would further be desirable for the stimulator to use periodic oroccasional sensing data to improve the treatment of diurnal GERD bydynamically detecting when a sensor is present, determining when asensor is transmitting, or capable of transmitting, data, and processingthe sensed data using an application having a special mode whichopportunistically uses the sensed data to change stimulation parameters.

It is also desirable to automate the setting or calibration of some orall device parameters in order to reduce the need for medical follow-upvisits, reduce burdens on healthcare providers and patients, decreasethe rate of programming mistakes, and improve outcomes, therebyimproving the treatment of diurnal GERD.

In addition, patients suffering from GERD, nocturnal GERD, diurnal GERD,or transient lower esophageal sphincter relaxation (tLESR), typicallyhave their eating habits impaired because of the associated refluxevents. As a result, these individuals often experience fluctuations inweight, or actively lose weight, since they are unable or unwilling toingest much food.

Although often not completely effective, conventional treatments, suchas the daily use of H2 receptor antagonists (H2RAs) or proton-pumpinhibitors (PPIs), may suppress acid reflux to some degree. In suchcases, a GERD patient may find that, as symptoms improve, he or shebegins to eat more and gain weight. Weight gain is therefore anunintended and undesirable consequence of conventional GERD treatments.

It is therefore also desirable to have a treatment for GERD, nocturnalGERD, diurnal GERD, or tLESR that, while successfully reducing oreliminating acid reflux, avoids or minimizes the weight gain whichtypically accompanies the successful treatment of acid reflux.

SUMMARY OF THE INVENTION

The present application is directed toward embodiments for achieving anyof the following therapeutic objectives: the treatment of diurnal GERD;esophageal reflux; esophageal motility disorders; esophageal neural,muscular or neuromuscular disorders; improving or normalizing apatient's LES function; treating a patient to improve or normalizeesophageal pH, wherein said improvement or normalization is achievedwhen a patient has an esophageal pH value of less than 4 for a period oftime no greater than 5%, 10%, or 50% of a 24 hour period or somefraction thereof; treating a patient to prevent damage to the patient'slower esophageal sphincter caused by acid reflux; treating a patient tomitigate damage to the patient's lower esophageal sphincter caused byacid reflux; treat esophago-gastric disorders; treating a patient tostop progression of damage to the patient's lower esophageal sphinctercaused by acid reflux; modifying or increasing LES pressure; modifyingor increasing esophageal body pressure; modifying or improvingesophageal body function; reducing incidents of heartburn; modifying orimproving esophageal acid exposure; modifying or improving esophagealclearance; modifying or improving the volume or the height of therefluxate; modifying or improving esophageal perception or sensation;increasing lower esophageal tone; detecting when a patient swallows;detecting when a patient is eating; detecting the LES pressure of apatient; treating a gastrointestinal condition of a patient; treating apatient to minimize the patient's consumption of certain solids orliquids; reducing patient symptoms associated with diurnal GERD whereinsuch reduction is measured by an improvement in a patient quality oflife survey and wherein said improvement is calculated by having apatient provide a first set of responses to said quality of life surveyprior to treatment and having a patient provide a second set ofresponses to said quality of life survey after said treatment andcomparing the first set of responses to said second set of responses;treating a patient for any of the above-listed therapeutic objectiveswith the additional requirement of avoiding tissue habituation, tissuefatigue, or certain adverse reactions, including, but not limited to,chest pain, difficulty in swallowing, pain associated with swallowing,heartburn, injury to surrounding tissue, or cardiac arrhythmias.

The above listed therapeutic objectives are achieved using a stimulator,including a macrostimulator or a microstimulator, that is adapted todeliver electrical stimulation, in accordance with a plurality ofelectrical stimulation parameters, to one or more of the followinganatomical areas: the lower esophageal sphincter; within 5 cm above orproximal to and/or 5 cm below or distal to the LES; proximate to theLES; in the vicinity of the LES; the esophageal body; the upperesophageal sphincter (UES); within, proximate to, or in the vicinity ofthe gastro-esophageal junction; the esophagus, including esophagealbody, LES, and UES; proximate to the esophagus; in the vicinity of theesophagus; at or within the stomach; nerves supplying the LES orgastro-esophageal junction; nerves supplying the esophageal body; nervessupplying the UES; nerves supplying the esophagus, including theesophageal body, LES, and UES; submucosa of organ systems, includingsubmucosa proximate to the LES, esophagus, gastrointestinal region, orUES to cause adjacent smooth muscle contraction using electrical fieldstimulation, and/or adjacent muscularis or serosa.

In one embodiment, a preferable microstimulator comprises an implantablestimulator device with permanently attached electrodes that are smallenough to be placed in the submucosal space of the LES via endoscopy,including less then 50 mm in length, less than 10 mm in width, and/orless than 10 mm in thickness.

In one embodiment, a preferable macrostimulator comprises an implantablestimulator device with a detachable stimulating lead and having a formfactor comparable to a conventional cardiac pacemaker orneurostimulator. The macrostimulator device is adapted to be implantedin a subcutaneous space in the muscularis or the serosa and configuredto have its lead pass through a patient's abdominal wall in order toattach electrodes to the patient's LES muscle tissue.

In one embodiment, the presently disclosed devices and treatmentmethodologies require less energy to operate and achieve atherapeutically effective result than prior art devices and treatmentmethodologies. In another embodiment, in patients with abnormal LESfunction, the presently disclosed devices and treatment methodologiesare able to cause within the patient sustained normalized LES function,improved LES function, or adequate LES function, even after electricalstimulation is terminated.

In one embodiment, the presently disclosed devices and treatmentmethodologies are able to cause, within the patient, a sustainedincrease in resting LES pressure, even after electrical stimulation isterminated. In another embodiment, the presently disclosed devices havea simplified design because, although used to treat patients sufferingfrom one of the plurality of ailments listed above, they do not requiresensing systems capable of sensing when a person is engaged in a wetswallow, including a swallow with a bolus volume of greater than 1 cc,do not require any energy storage components, such as capacitors orbatteries, local to the electrical stimulator, and/or are able to havesmaller size and energy storage requirements relative to the prior art.In another embodiment, the presently disclosed devices and treatmentmethodologies result in an improved therapeutic experience for thepatient because they avoid causing UES, esophagus or LES muscle fatigueand/or dysphagia, and, furthermore, operate in stimulation ranges thatminimize the likelihood of the patient feeling any pain or unpleasantsymptoms during electrical stimulation.

In one embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives byapplying electrical stimulation to the LES and terminating theelectrical stimulation, whereby the stimulation causes the patient's LESfunction measured using a plurality of parameters, including LESpressure or function, to improve or normalize during stimulation and/orfor some duration after stimulation is terminated.

In one embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives byapplying electrical stimulation to the LES and terminating theelectrical stimulation, whereby the stimulation causes the patient's LESfunction measured using a plurality of parameters, including LESpressure, to improve to a sufficient level to achieve one or more of theaforementioned therapeutic objectives during stimulation and/or for someduration after stimulation is terminated.

In one embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives byapplying electrical stimulation to the LES and terminating theelectrical stimulation, whereby the stimulation causes the patient's LESfunction measured using a plurality of parameters, including LESpressure, to improve at least 10% during stimulation and/or for someduration after stimulation is terminated.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives byapplying electrical stimulation to the LES and terminating theelectrical stimulation, whereby the stimulation causes the patient's LESpressure to increase during stimulation and/or for some duration afterstimulation is terminated.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives byapplying electrical stimulation to the LES and terminating theelectrical stimulation, whereby the stimulation causes the patient'sesophageal acid exposure to improve during stimulation and/or for someduration after stimulation is terminated.

In one embodiment, the stimulation is designed to produce an increase inresting LES tone without impacting the ability of the LES to relax,thereby improving patient comfort and avoiding symptoms, such asdysphagia.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve the above described LES pressureincreases and normalization of function, post-stimulation, without anylocal energy storage components, such as batteries or capacitors. In oneembodiment, the electrical stimulation system comprises amicrostimulator as described in U.S. Pat. No. 7,702,395, U.S. patentapplication Ser. Nos. 10/557,362 and 12/598,871, and PCT ApplicationNumbers PCT/US09/55594 and PCT/US10/35753, which are herein incorporatedby reference.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve the above described LES pressureincreases and normalization of function, post-stimulation, using aminimal energy storage for pulse shaping, where the minimal energystorage is capable of storing greater than 0 electrons but less thanapproximately 100 of electrons at a voltage of 1 V to 10V, preferably2.5 V to 4.5 V.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve the above described LES pressureincreases and normalization of function, post-stimulation, without anylocal sensing components capable of sensing a wet swallow, a feed phase,or when the patient is engaged in, or about to be engaged in,propagating a bolus through his esophagus.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives byoperating the electrical stimulation device, in a given 24 hour period,less than 100% of the time, in a non-continuous or duty cycled manner,less than 100% of the 24 period, up to a predefined percentage of a timeperiod, such as 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5% orany increment therein, up to a maximum “on” period, such as 12 hours,during which the device may be continually operating, or up to a maximum“off” period, such as 12 hours, during which the device is notoperating. In one embodiment the “on” period of the device is same orless than the “off” period of the device. In another embodiment the “on”period of the device is more than the “off” period of the device.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives bymeasuring a multitude of parameters, inputting said parameters into analgorithm, and initiating, terminating, or otherwise modifyingelectrical stimulation to the LES based upon a summary score calculatedby said algorithm where said algorithm may be implemented in either thestimulator or a separate system.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives bymeasuring a multitude of parameters, inputting said parameters into analgorithm, and initiating, terminating, or otherwise modifyingelectrical stimulation to the LES based upon a summary score calculatedby said algorithm. The algorithm can be executed independent of theoperation of the stimulation system and, in particular, need not beoperated in real-time to modify stimulation based on detected events.The algorithm can be executed offline, either locally or remotely, withthe results of said execution then being used to modify the electricalstimulation pattern at some later point in time. The algorithm can beexecuted completely or partially outside the electrical stimulationsystem in a patient device or programming device external to thepatient's body and then wirelessly communicated back to the electricalstimulation system.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives bymeasuring the amount of time a patient spends in the supine positionthrough the use of an accelerometer and/or inclinometer, and applying anelectrical stimulation to the LES based upon this measured time.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward electrical stimulation systems andtreatment methods that achieve above-listed therapeutic objectives in amanner that minimizes LES muscle fatigue, minimizes energetic demand ofthe therapy and minimizes uncomfortable sensation or pain experienced bythe patient that may be caused by electrically stimulating the LES.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward systems for stimulating an anatomicalstructure within a patient, comprising a stimulator adapted to beimplanted into the patient and a sensor adapted to be implanted into thepatient separate from said stimulator, wherein the sensor is configuredto sense a physiological parameter of the patient and communicate dataindicative of said physiological parameter to the stimulator or analysissystem and wherein said stimulator is programmed to modify at least onestimulation parameter based upon said data.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward systems for stimulating an anatomicalstructure within a patient, comprising a stimulator adapted to beimplanted into the patient and a sensor adapted to be implanted into thepatient, wherein the sensor is configured to sense a physiologicalparameter of the patient, is in wired or wireless communication with thestimulator, and communicates data indicative of said physiologicalparameter to the stimulator and wherein said stimulator is programmed tomodify at least one stimulation parameter based upon said data.

In another embodiment, the presently disclosed devices and treatmentmethodologies are directed toward systems for stimulating an anatomicalstructure within a patient, comprising a stimulator with a receiver toreceive data from a sensor, and a control unit that analyzes thereceived data and adjusts at least one stimulation parameter. Thestimulator minimally comprises a structure that houses stimulatingcircuitry and a means to adjust said at least one stimulation parameter.The stimulating circuitry comprises a power source and means fordelivering stimulation. The means for delivering stimulation include aplurality of electrical contacts. In one embodiment, the sensor isadapted to measure pressure or impedance and transmit the pressure orimpedance data to the stimulator via uni-directional or bi-directionalcommunications.

Optionally, either the stimulator or an external system comprises areceiver to receive said data from the sensor, and a control unit thatanalyzes the received data and adjusts said at least one stimulationparameter. The stimulator minimally comprises a structure that housesstimulating circuitry and a means to adjust said at least onestimulation parameter. The stimulating circuitry comprises a powersource and means for delivering stimulation. The means for deliveringstimulation include a plurality of electrical contacts. In oneembodiment, the sensor is a pH capsule. The sensor is adapted to measurephysiological pH and transmit pH data from within a lumen of thepatient's esophagus. The sensor may be located within a nasogastric tubeor catheter and may transmit pH data to the stimulator viauni-directional or bi-directional communications.

Optionally, the stimulator comprises a controller that is adapted toexecute a plurality of programmatic instructions to adjust the at leastone stimulation parameter based upon data, such as pH data. The pH datais continuously streamed to the stimulator from a pH capsule. Thecontroller adjusts one or more stimulation parameters to increase astimulation dose to the patient if, within a predefined period, the pHdata is less than a first threshold value for a percentage of timehigher than a second threshold value. For example, the first thresholdis a pH of 4 and the second threshold is 5-100 percent of a pH valuedetermined pursuant to a 24-hour recording. The stimulation parametersinclude the number of stimulations in a given period of time and/or theduration of each stimulation event. At least one of said stimulationparameters is bounded by a maximum value. At least one of saidstimulation parameters is bounded by a minimum value.

Optionally, the controller adjusts one or more stimulation parameters todecrease a stimulation dose to the patient if, within a predefinedperiod, the esophageal pH data is less than a first threshold value fora percentage of time less than a second threshold value. For example,the first threshold is a pH of 4 and the second threshold is 0-5 percentof a pH value determined pursuant to a 24-hour recording. Thestimulation parameters include the number of stimulations in a givenperiod of time and/or the duration of each stimulation event and/oramplitude of the stimulation. At least one of said stimulationparameters is bounded by a maximum value. At least one of saidstimulation parameters is bounded by a minimum value.

Optionally, the stimulator comprises a controller that is adapted toexecute a plurality of programmatic instructions to adjust said at leastone stimulation parameter based upon data, wherein the data comprises atleast one of pH data, pressure data, accelerometer data, inclinometerdata, impedance data or a combination thereof. One of ordinary skill inthe art would appreciate that other sensing, patient inputs or userinputs can be used to adjust the stimulation parameters. The data istransmitted from the stimulator or directly from the sensor to a devicewhich is located external to the patient.

In one embodiment, the transmission occurs automatically when thepatient and external device are within a predefined proximity. Inanother embodiment, the transmission is enabled when the patient andexternal device are within a predefined proximity and only occurs whenexpressly authorized by the patient. The external device is adapted toreceive data indicative of stimulation parameters from a second externaldevice and communicate the data indicative of stimulation parameters tothe stimulator within the patient.

In one embodiment, the second external device can be combined with, andhoused within the first external device. The stimulator comprises acontroller that is adapted to monitor a status of the sensor. In anotherembodiment, the controller adapted to monitor a status of the sensor islocated in an external device. If said sensor fails to respond tocommunication attempts from said controller or said sensor fails adiagnostic test, the controller generates a signal indicative of asensor failure state. If said controller receives data indicating thesensor has migrated from a desired position to an undesired position,the controller generates a signal indicative of a sensor failure state.The data indicating the sensor has migrated from a desired position toan undesired position includes pH less than a threshold value forgreater than a predefined a period of time.

Optionally, the stimulator comprises a structure that houses stimulatingcircuitry, a receiving antenna to receive the data from the sensor, anda control unit that analyzes the received data and adjusts said at leastone stimulation parameter. The receiving antenna can be additionallyused to enable energy transfer to said stimulator. The sensor comprisesa local energy source and is adapted to transfer energy from said sensorto the stimulator. One embodiment of the sensor is a pH capsule or a pHsensor anchored to a nasogastric tube or catheter. In anotherembodiment, the sensor may be powered by an energy source external tothe patient.

In another embodiment, the presently disclosed devices stimulate ananatomical structure within a patient and comprise a stimulator adaptedto be implanted into the patient and a sensor adapted to be temporarilypositioned within a lumen of the patient separate from the stimulator,wherein the sensor is configured to sense a physiological parameter ofthe patient and communicate data indicative of the physiologicalparameter to the stimulator and wherein the stimulator is programmed tomodify at least one stimulation parameter based upon the data.

In another embodiment, the presently disclosed devices collect data fromwithin a patient and transmit the data outside the patient's body andcomprise a logging device adapted to be implanted into the patient,wherein the logging device comprises a memory adapted to store aplurality of data; and a sensor adapted to be temporarily implanted intoa lumen of the patient separate from the logging device, wherein thesensor is configured to sense a physiological parameter of the patientand communicate the sensed data to the logging device and wherein thelogging device is capable of storing the sensed data and wirelesslytransmitting sensed data to a receiver located outside the body.

In another embodiment, the present device and treatment treats abnormalesophageal acid exposure or diurnal GERD symptoms without increasing theLES pressure or tone but by preventing tLESR, increasing esophagealaccommodation, diminishing the volume of refluxate or alteringperception of esophageal symptoms caused by the refluxate.

In another embodiment, the present specification is directed toward asystem for increasing pressure or improving function of a patient'slower esophageal sphincter (LES), comprising: at least one electrodepositioned proximate the LES; a waveform generator operably coupled tosaid at least one electrode; a controller configured to electricallystimulate the LES to increase the pressure or improve the function ofthe LES, and maintain an average pressure of the LES above a pressure orfunction level which reduces at least one of a frequency or duration ofoccurrence or an intensity of acid reflux symptoms in the patient duringand/or after stimulation by controlling the waveform generator torepeatedly: generate and apply an electrical pulse train to the LESthrough the electrodes for a stimulation period, and terminate theelectrical pulse train for a rest period; and, an accelerometer coupledto the controller for sensing posture data of the patient, wherein saidcontroller is configured to control the waveform generator to adjustparameters of the electrical pulse train applied to the LES based on ananalysis of said posture data from said accelerometer.

In another embodiment, the present specification is directed toward amethod for increasing pressure or improving function of a patient'slower esophageal sphincter (LES), comprising the steps of: providing animplantable pulse generator (IPG) comprising at least one electrodeoperably connected to a waveform generator; implanting said IGP within apatient such that said at least one electrode is positioned proximatesaid LES; providing a controller configured to electrically stimulatethe LES to increase the pressure of the LES, and maintain an averagepressure of the LES above a pressure level or LES function above apredefined function level which reduces at least one of a frequency orduration of occurrence or an intensity of acid reflux symptoms in thepatient during and/or after stimulation by controlling the waveformgenerator to repeatedly: generate and apply an electrical pulse train tothe LES through the electrodes for a stimulation period, and terminatethe electrical pulse train for a rest period; and, providing anaccelerometer coupled to the controller for sensing posture data of thepatient, wherein said controller is configured to control the waveformgenerator to adjust parameters of the electrical pulse train applied tothe LES based on an analysis of said posture data from saidaccelerometer.

In one embodiment, the method for increasing pressure of a patient'slower esophageal sphincter (LES) further comprises the step of switchingthe controller from a first stimulation mode to a second stimulationmode when the posture data crosses a predetermined threshold value. Inone embodiment, the posture data comprises time spent in a supineposition and the threshold value is set to 1, 5, 30, or 60 minutes. Inanother embodiment, the posture data comprises level of inclination to ahorizontal position and the threshold value is set to 140, 150, 160, or170 degrees.

In one embodiment, the first stimulation mode comprises a dose mode andthe second stimulation mode comprises a cyclic mode, wherein the dosemode provides a pre-programmed stimulation session based on the time ofday (e.g. 7 AM, 9:30 AM, 1:30 PM, etc) while the cyclic mode provides astimulation session regularly spaced over a given period of time (e.g.every 2 hours our every 3 hours).

In one embodiment, the method for increasing pressure or improvingfunction of a patient's lower esophageal sphincter (LES) furthercomprises the step of applying a block time after entering the secondstimulation mode, during which no further stimulations can be applied,wherein any stimulation begun before entering the second stimulationmode is allowed to complete before initiating the block time.

In one embodiment, the method for increasing pressure or improvingfunction of a patient's lower esophageal sphincter (LES) furthercomprises the step of switching the controller from the secondstimulation mode to the first stimulation mode when the posture datadrops below the predetermined threshold value.

In another embodiment, the present specification is directed toward asystem for increasing pressure or improving function of a patient'slower esophageal sphincter (LES), comprising: at least one electrodepositioned proximate the LES; a waveform generator operably coupled tosaid at least one electrode; a controller configured to electricallystimulate the LES to increase the pressure or improve the function ofthe LES, and maintain an average pressure or function of the LES above apressure or function level which reduces at least one of a frequency orduration of occurrence or an intensity of acid reflux symptoms in thepatient both during and after stimulation by controlling the waveformgenerator to repeatedly: generate and apply an electrical pulse train tothe LES through the electrodes for a stimulation period, and terminatethe electrical pulse train for a rest period; and, an impedance sensorcoupled to the controller for sensing impedance values in the LES,wherein said controller is configured to control the waveform generatorto adjust parameters of the electrical pulse train applied to the LESbased on an analysis of said impedance values from said sensor.

In another embodiment, the present specification is directed toward amethod for increasing pressure or improving function of a patient'slower esophageal sphincter (LES), comprising the steps of: providing animplantable pulse generator (IPG) comprising at least one electrodeoperably connected to a waveform generator; implanting said IGP within apatient such that said at least one electrode is positioned proximatesaid LES; providing a controller configured to electrically stimulatethe LES to increase the pressure or improve the function of the LES, andmaintain an average pressure or function of the LES above a pressure orfunction level which reduces at least one of a frequency of occurrenceor an intensity of acid reflux symptoms in the patient both during andafter stimulation by controlling the waveform generator to repeatedly:generate and apply an electrical pulse train to the LES through theelectrodes for a stimulation period, and terminate the electrical pulsetrain for a rest period; and, providing an impedance sensor coupled tothe controller for sensing impedance values in the LES, wherein saidcontroller is configured to control the waveform generator to adjustparameters of the electrical pulse train applied to the LES based on ananalysis of said impedance values from said sensor.

In one embodiment, sensing and analysis of the impedance valuescomprises the following steps: recording six impedance measurements insuccession prior to each stimulation session; discarding the high andlow measurement values; averaging the remaining four values to calculatean average or a variability index; and, modifying stimulation parametersbased on said average or variability index.

In one embodiment, the step of modifying the stimulation parameterscomprises modifying stimulation voltage amplitude to maintain a givencurrent (mA). The voltage amplitude is bound by a maximum stimulationamplitude, a minimum stimulation amplitude, and/or a maximum allowablechange in stimulation amplitude. If the initial six impedancemeasurements are determined to be inappropriate, the stimulationparameters are not modified and impedance measurements are retaken aftera predetermined period of time. In one embodiment, the predeterminedperiod of time is 5 minutes.

In one embodiment, the present specification is directed toward a systemfor increasing pressure or improving function of a patient's loweresophageal sphincter (LES), comprising: at least one electrodepositioned proximate the LES; a waveform generator operably coupled tosaid at least one electrode; a controller configured to electricallystimulate the LES to increase the pressure or improve the function ofthe LES, and maintain an average pressure or function of the LES above apressure or function level which reduces at least one of a frequency orduration of occurrence or an intensity of acid reflux symptoms in thepatient both during and after stimulation by controlling the waveformgenerator to repeatedly: generate and apply an electrical pulse train tothe LES through the electrodes for a stimulation period, and terminatethe electrical pulse train for a rest period; an accelerometer coupledto the controller for receiving signals from an external device, whereinsaid controller is configured to control the waveform generator toadjust parameters of the electrical pulse train applied to the LES basedon predetermined patterns received by said accelerometer; and, anexternal device capable of transmitting signals to said accelerometerbased on input from the patient.

In one embodiment, the external device comprises a battery poweredvibratory device comprising at least one patient operable button and thetransmitting signals comprise a multitude of vibratory signals ofdiffering frequencies. In one embodiment, the vibratory device comprisesa first start/stop button for symptoms, a second start/stop button fordrink times, and a third start/stop button for meal times.

In another embodiment, an accelerometer is coupled to the controller forreceiving vibratory signals generated by patient taps on the skinsurface proximate the implantation location of the IPG, wherein one tapcauses said device to generate a signal indicative of a drink time, twotaps causes said device to generate a signal indicative of a meal time,and three taps causes said device to generate a signal indicative ofsymptoms.

In yet another embodiment, the present specification is directed towarda method for increasing pressure of a patient's lower esophagealsphincter (LES), comprising the steps of: providing an implantable pulsegenerator (IPG) comprising at least one electrode operably connected toa waveform generator; implanting said IPG within a patient such thatsaid at least one electrode is positioned proximate said LES; providinga controller configured to electrically stimulate the LES to increasethe pressure or improve the function of the LES, and maintain an averagepressure or function of the LES above a pressure or function level whichreduces at least one of a frequency or duration of occurrence or anintensity of acid reflux symptoms in the patient both during and afterstimulation by controlling the waveform generator to repeatedly:generate and apply an electrical pulse train to the LES through theelectrodes for a stimulation period, and terminate the electrical pulsetrain for a rest period; and, providing an accelerometer coupled to thecontroller for receiving signals from an external device, wherein saidcontroller is configured to control the waveform generator to adjustparameters of the electrical pulse train applied to the LES based onpredetermined patterns received by said accelerometer; providing anexternal device capable of transmitting signals to said accelerometerbased on input from the patient; placing the external device against thepatient's body proximate the implantation location of said IPG; andactivating said external device wherein said activation results intransmission of signals from said external device to said accelerometer.

In one embodiment, the external device comprises a battery poweredvibratory device comprising at least one patient operable button andsaid transmitting signals comprise a multitude of vibratory signals ofdiffering frequencies. Activating the external device comprises havingthe patient press said at least one patient operable button in apredetermined manner based on a symptom or a symptom triggering event.In one embodiment, the vibratory device comprises a first start/stopbutton for symptoms, a second start/stop button for drink times, and athird start/stop button for meal times. The patient presses theappropriate start/stop button for the current symptom or symptomtriggering event for a predetermined period of time. In one embodiment,the predetermined period of time is 15 seconds. In another embodiment,the vibratory device comprises a single patient operable button, whereinone tap of said button signifies a drink time, two taps of said buttonsignify a meal time, and three taps of said button signify symptoms, thepatient taps the single patient operable button the appropriate numberof times for the current symptom or symptom triggering event.

In one embodiment, the present specification discloses a system fortreating a patient with gastroesophageal reflux disease, comprising: atleast one electrode positioned within 3 cm above and 3 cm below thepatient's lower esophageal sphincter (LES); a waveform generatoroperably coupled to said at least one electrode; a controller configuredto electrically stimulate the LES to increase the pressure or functionof the LES from a first level to a second level, wherein said increasein LES pressure or function above the first level occurs duringstimulation and continues after stimulation ceases and wherein saidcontroller controls the waveform generator to repeatedly: a) generateand apply an electrical pulse train to the LES through the at least oneelectrode for a stimulation period, and b) terminate the electricalpulse train for a rest period.

Optionally, the second level is a pressure or function level thatreduces at least one of a frequency or duration of occurrence or anintensity of acid reflux symptoms in the patient. The electrical pulsetrain is between 3 mA to 8 mA. The stimulation period is between 5 to 60minutes in length. The controller is programmed to generate and apply anelectrical pulse train to the LES for 4 to 24 stimulation periods perday, wherein each stimulation period is separated by a rest period. Thecontroller is programmed to generate an on period of 0.1 seconds to 60seconds and an off period of 0.1 seconds to 60 seconds within a cycleperiod of 24 hours or more. The electrical pulse train consists ofpulses with frequencies between 10 Hz and 200 Hz. The electrical pulsetrain consists of pulse widths ranging from 100 to 1000 μsec. Thecontroller is programmed to generate and apply an electrical pulse trainto the LES for more than 11 stimulation periods per day, wherein eachstimulation period is separated by a rest period and wherein eachstimulation period consists of electrical pulses that are less than 3mA. The stimulation period consists of electrical pulses that are lessthan 3 mA being applied for a period of time longer than 10 minutes.

Optionally, the system further comprises an accelerometer coupled to thecontroller for sensing posture data of the patient, wherein saidcontroller is configured to control the waveform generator to adjustparameters of the electrical pulse train applied to the LES based on ananalysis of said posture data from said accelerometer. The controller isconfigured to switch from a first stimulation mode to a secondstimulation mode when said posture data crosses a predeterminedthreshold value. The posture data comprises time spent in a supineposition and said threshold value is set to 1, 5, 30, or 60 minutes. Theposture data comprises level of inclination to a horizontal position andsaid threshold value is set to 140, 150, 160, or 170 degrees. The firststimulation mode comprises a dose mode which provides a pre-programmedstimulation session per time of day and said second stimulation modecomprises a cyclic mode which provides a stimulation session regularlyspaced over a given period of time. The controller is configured toapply a block time after entering said second stimulation mode, whereinno further stimulations are applied during said block time and whereinany stimulation begun before entering said second stimulation mode isallowed to complete before initiating said block time. The controller isconfigured to switch from a second stimulation mode to a firststimulation mode when said posture data crosses a predeterminedthreshold value. The controller is configured to apply a block timeafter entering said first stimulation mode, wherein no furtherstimulations are applied during said block time and wherein anystimulation begun before entering said first stimulation mode is allowedto complete before initiating said block time.

Optionally, the system further comprises an impedance sensor coupled tothe controller for sensing impedance values in the LES, wherein saidcontroller is configured to control the waveform generator to adjustparameters of the electrical pulse train applied to the LES based onsaid impedance values from said sensor. The system senses and analyzessaid impedance values by recording more than two impedance measurementsin succession prior to each stimulation session, discarding the high andlow measurement values, checking for inappropriate values, and averagingthe remaining values to modify stimulation parameters based on saidaverage. The system modifies stimulation parameters by modifyingstimulation voltage amplitude to deliver a consistent current (mA). Thevoltage amplitude is bound by a maximum stimulation amplitude, a minimumstimulation amplitude, and/or a maximum allowable change in stimulationamplitude. The system senses and analyzes said impedance values byrecording more than two impedance measurements in succession prior toeach stimulation session, discarding the high and low measurementvalues, checking for inappropriate values, averaging the remainingvalues, and retaking impedance measurements after a predetermined periodof time if said four impedance measurements are determined to be tooinappropriate. The predetermined period of time is 5 minutes.

Optionally, the system further comprises a device external to thepatient, wherein said device is capable of transmitting signals based oninput from the patient, and an accelerometer coupled to the controllerfor receiving signals from the external device, wherein said controlleris configured to control the waveform generator to adjust parameters ofthe electrical pulse train applied to the LES based on signals receivedby said accelerometer. The external device comprises a vibratory devicehaving at least one patient operable button and configured to transmitsignals comprising a multitude of vibratory signals of differingfrequencies. The vibratory device comprises a first start/stop buttonfor symptoms, a second start/stop button for drink times, and a thirdstart/stop button for meal times. The external device is configured totransmit vibratory signals to said accelerometer when said externaldevice is placed against the patient's body proximate the implantationlocation of said IPG and activated to cause a transmission of signalsfrom said external device to said accelerometer.

Optionally, the system further comprises an accelerometer coupled to thecontroller for receiving vibratory signals generated by patient taps onthe skin surface proximate the implantation location of the IPG, whereinone tap causes said device to generate a signal indicative of a drinktime, two taps causes said device to generate a signal indicative of ameal time, and three taps causes said device to generate a signalindicative of symptoms.

In another embodiment, the present specification discloses a method oftreating a patient with gastroesophageal reflux disease (GERD), whereinsaid patient has a lower esophageal sphincter (LES), the methodcomprising: stimulating the LES by applying an electrical pulse in amanner that increases or accelerates the patient's sense of satietyrelative to the patient's sense of satiety in the absence of stimulationwhile concurrently improving LES function, tone and/or pressure.

In another embodiment, the present specification discloses a method oftreating a patient with GERD, wherein said patient has a loweresophageal sphincter (LES), the method comprising: stimulating the LESby applying an electrical pulse in a manner that causes a patient to eatmore slowly relative to the patient's rate of eating in the absence ofstimulation while concurrently improving LES function, tone and/orpressure.

In another embodiment, the present specification discloses a method oftreating a patient with GERD, wherein said patient has a loweresophageal sphincter (LES), the method comprising: reducing funduscompliance by stimulating an area proximate the LES, wherein saidreduction of fundus compliance increases or accelerates the patient'ssense of satiety relative to the patient's sense of satiety in theabsence of stimulation and wherein said stimulation improves thefunction, pressure, and/or tone of the LES.

In another embodiment, the present specification discloses a method oftreating a patient with GERD, wherein said patient has a loweresophageal sphincter (LES), the method comprising: reducing funduscompliance by stimulating an area proximate the LES, wherein saidreduction of fundus compliance causes a patient to eat more slowlyrelative to the patient's rate of eating in the absence of stimulationand wherein said stimulation improves the function, pressure, and/ortone of the LES.

In another embodiment, the present specification discloses a method oftreating a patient with GERD, wherein said patient has a loweresophageal sphincter (LES), the method comprising: neurologicallymodulating gastric pressure by stimulating an area proximate the LES,wherein said neurological modulation of gastric pressure increases oraccelerates the patient's sense of satiety relative to the patient'ssense of satiety in the absence of stimulation and wherein saidstimulation improves the function, pressure, and/or tone of the LES.

In another embodiment, the present specification discloses a method oftreating a patient with GERD, wherein said patient has a loweresophageal sphincter (LES), the method comprising: neurologicallymodulating gastric pressure by stimulating an area proximate the LES,wherein said neurological modulation of gastric pressure causes apatient to eat more slowly relative to the patient's rate of eating inthe absence of stimulation and wherein said stimulation improves thefunction, pressure, and/or tone of the LES.

In another embodiment, the present specification discloses a method ofassisting a patient in losing weight, the method comprising:neurologically modulating gastric pressure by stimulating an areaproximate the patient's lower esophageal sphincter, wherein saidneurological modulation of gastric pressure causes a patient to eat moreslowly relative to the patient's rate of eating in the absence ofstimulation.

In another embodiment, the present specification discloses a method ofassisting a patient in losing weight, the method comprising:neurologically modulating gastric pressure by stimulating an areaproximate the patient's lower esophageal sphincter, wherein saidneurological modulation of gastric pressure increases or accelerates thepatient's sense of satiety relative to the patient's sense of satiety inthe absence of stimulation.

In another embodiment, the present specification discloses a method ofassisting a patient in losing weight, the method comprising: reducingfundus compliance by stimulating an area proximate the patient's loweresophageal sphincter, wherein said reduction of fundus compliance causesa patient to eat more slowly relative to the patient's rate of eating inthe absence of stimulation.

In another embodiment, the present specification discloses a method ofassisting a patient in losing weight, the method comprising: reducingfundus compliance by stimulating an area proximate the LES, wherein saidreduction of fundus compliance increases or accelerates the patient'ssense of satiety relative to the patient's sense of satiety in theabsence of stimulation.

In another embodiment, the present specification discloses a method ofassisting a patient in losing weight, the method comprising: stimulatingan area proximate the LES, wherein said stimulation increases oraccelerates the patient's sense of satiety relative to the patient'ssense of satiety in the absence of stimulation.

In another embodiment, the present specification discloses a method ofassisting a patient in losing weight, the method comprising: stimulatingan area proximate the LES, wherein said stimulation causes a patient toeat more slowly relative to the patient's rate of eating in the absenceof stimulation.

Optionally, in any of the aforementioned methods, the area proximate theLES is within 1-3 cm of the LES. Optionally, in any of theaforementioned methods, the stimulation does not cause the patient tosuffer or experience dysphagia. Optionally, in any of the aforementionedmethods, the stimulation is performed continuously. Optionally, in anyof the aforementioned methods, the stimulation is performedintermittently.

These and other embodiments shall be discussed in greater detail belowand in relation to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects and advantages of the presently disclosedtreatment methodologies, devices, and systems will become more fullyapparent from the following detailed description when read inconjunction with the accompanying drawings with like reference numeralsindicating corresponding parts through-out, wherein:

FIG. 1 depicts the physiology of a normal swallow;

FIG. 2 depicts a wet swallow at baseline for a GERD patient;

FIG. 3 depicts a wet swallow with stimulation;

FIG. 4 depicts one exemplary pressure profile, both during stimulationand post-stimulation;

FIG. 5 depicts another exemplary pressure profile, both duringstimulation and post-stimulation;

FIG. 6 depicts another exemplary pressure profile, both duringstimulation and post-stimulation;

FIG. 7 depicts yet another exemplary pressure profile, both duringstimulation and post-stimulation;

FIG. 8 is a schematic of modulated pulse trains;

FIG. 9 is an illustration of a timeline depicting a stimulation sessionfollowed by a supine refractory time period;

FIG. 10 is an illustration of a timeline depicting a stimulation sessiontriggered by supine stimulation mode followed by a supine cancel period;

FIG. 11 depicts one exemplary electrode configuration in the esophagusof a patient;

FIG. 12 depicts another exemplary electrode configuration in theesophagus of a patient;

FIG. 13 depicts another exemplary electrode configuration in theesophagus of a patient;

FIG. 14 is a cross-sectional illustration of the upper gastrointestinaltract showing a pH sensing capsule in the esophagus and a stimulatoradapted to be implanted within the tissue of the patient;

FIG. 15 is a flow sheet depicting a certain parameter setting method ofone embodiment of the present invention;

FIG. 16 is a first embodiment of a block diagram of certain modules ofthe present invention;

FIG. 17 is a second embodiment of a block diagram of certain modules ofthe present invention;

FIG. 18 is a third embodiment of a block diagram of certain modules ofthe present invention;

FIG. 19 is a fourth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 20 is a fifth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 21 is a sixth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 22 is a seventh embodiment of a block diagram of certain modules ofthe present invention;

FIG. 23 is a eighth embodiment of a block diagram of certain modules ofthe present invention;

FIG. 24 is a graph relating pressure increases to baseline, stimulation,and post-stimulation periods;

FIG. 25 is a graph showing an improved LES pressure profile over time;

FIG. 26 is a graph showing a decrease in esophageal acid exposure overtime;

FIG. 27 is a graph showing a decrease in adverse symptoms over time;

FIG. 28 is a graph showing an improved LES pressure profile over time;and,

FIG. 29 is a flowchart detailing one embodiment of a method of treatingGERD and simultaneously increasing satiety in a patient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed toward programmable implantableelectro-medical device for the treatment of diurnal gastro-esophagealreflux disease (GERD). The electro-medical device of the presentinvention employs stimulators, including macrostimulators ormicrostimulators, which can be implanted with minimal invasiveness inthe gastrointestinal system. Specifically, these devices can bebeneficial for deep implant locations for which there is a naturalorifice access providing closer proximity than from outside the body. Itshould further be appreciated that the present device is capable ofstimulating all smooth muscle, not limited to GI smooth muscles and thatthe present device can be used to deliver stimulation to the proximalstomach or area adjacent to the proximal stomach for treating variousdiseases that can be affected by gastric stimulation such as gastricmotility problems and diabetes. The present application furtherincorporates by reference U.S. Pat. No. 6,901,295, PCT/US08/56479, andU.S. patent application Ser. Nos. 12/030,222, 11/539,645, and 12/359,317in their entirety.

For the purposes of this invention the lower esophageal sphincter (LES)encompasses the gastrointestinal structures at least 5 cm above or belowthe gastroesophageal junction, the Z-line or the squamocolumnar junctionand encompasses the structures of distal esophagus, gastroesophagealjunction, cardia and cardia or cardiac sphincter.

The systems and methods disclosed herein can be used to achieve aplurality of different therapeutic objectives: treatment of diurnalGERD; improving or normalizing a patient's LES function; treatment ofhypotensive LES; increase resting or baseline LES pressure; treating apatient to improve or normalize esophageal pH, wherein said improve ornormalization is achieved when a patient has an esophageal pH value ofless than a predefined value, for example, <4, 5, 6 or 7 for a period oftime no greater than 5%, 10%, or 15% of a 24 hour period or somefraction thereof; treating a patient to improve or normalize esophagealpH when in the supine position, wherein said improvement ornormalization is achieved when a patient has an esophageal pH value ofless than 4 for a period of time no greater than 5% of a 24 hour period;treating a patient to prevent damage to the patient's esophagus causedby acid reflux; treatment of supine position induced diurnal GERD;treatment of activity-induced diurnal GERD; prevention of supineposition induced diurnal GERD; prevention of activity-induced diurnalGERD; treating a patient to mitigate damage to the patient's esophaguscaused by acid reflux; treating a patient to stop progression of damageto the patient's esophagus caused by acid reflux; treating a patient tominimize transient relaxations of the patient's esophagus; modifying orincreasing LES pressure; modifying or increasing esophageal bodypressure; modifying or improving esophageal body function; modifying orimproving esophageal sensation induced by the refluxate; modifying orimproving the volume of refluxate; modifying or improving the proximatelevel of refluxate; modifying or improving the clearance of therefluxate; reducing incidents or severity of heartburn; modifying orimproving esophageal acid exposure; increasing lower esophageal tone;detecting when a patient swallows; detecting when a patient is eating;treating a gastrointestinal condition of a patient; treating a patientto minimize the patient's consumption of certain solids or liquids;reducing patient symptoms associated with diurnal GERD wherein suchreduction is measured by an improvement in a patient quality of lifesurvey and wherein said improvement is calculated by having a patientprovide a first set of responses to said quality of life survey prior totreatment and having a patient provide a second set of responses to saidquality of life survey after said treatment and comparing the first setof responses to said second set of responses; treating a patient for anyof the above-listed therapeutic objectives with the additionalrequirement of avoiding tissue habituation, tissue fatigue, tissueinjury or damage, or certain adverse reactions, including, but notlimited to, chest pain, difficulty in swallowing, pain associated withswallowing, heartburn, injury to surrounding tissue, or arrhythmias.

The disclosed treatment methods may be practiced within, and devices maybe implanted within, a plurality of anatomical regions to achieve one ormore of the therapeutic objectives described above. Treatment sites, orimplantation sites, include: the lower esophageal sphincter; within 5 cmabove and 5 cm below the LES, gastroesophageal junction, squamocolumnarjunction or the Z-line; proximate to the LES, gastroesophageal junction,squamocolumnar junction or the Z-line; in the vicinity of the LES,gastroesophageal junction, squamocolumnar junction or the Z-line; theesophageal body; the upper esophageal sphincter (UES); within, proximateto, or in the vicinity of the gastro-esophageal junction; the esophagus,including esophageal body, LES, and UES; proximate to the esophagus; inthe vicinity of the esophagus; at or within the stomach; nervessupplying the LES or gastro-esophageal junction; nerves supplying theesophageal body; nerves supplying the UES; or nerves supplying theesophagus, including the esophageal body, LES, and UES.

Additionally, it should be appreciated that a therapy which requires alower amount of energy increases the long-term functionality of astimulation device. Furthermore, accurate implantation of electrodes isimperative for improved efficacy and safety of these devices. Submucosaof organ systems, such as the area within the gastrointestinal tractbetween the muscularis mucosa and muscularis propria (two high impedancelayers), have a relatively lower electrode-tissue interface impedance(referred to as impedance herein) and are therefore desirable locationsfor lead implantation and improved efficacy of stimulation. In addition,the loose connective tissue of the submucosa provides an improvedenvironment for tunneling and creating pockets for lead implantation andmicrostimulator implantation.

In one embodiment, the macrostimulator, microstimulator or theirrespective electrodes are implanted in the submucosa proximate to theLES, esophagus, or UES to cause adjacent smooth muscle contraction usingelectrical field stimulation. Additional stimulator structures and/orelectrodes may be placed in the adjacent muscularis or serosa and usedin combination with the aforementioned macrostimulator ormicrostimulator. In another embodiment, the stimulator or electrodes areimplanted in the gastrointestinal submucosa to cause gastrointestinalmuscle contraction using electrical field stimulation. Additionalstimulator structures and/or electrodes may be placed or proximate to inthe adjacent gastrointestinal muscularis mucosa, gastrointestinalserosa, or gastrointestinal nerves.

The present specification is also directed toward methods and systemsfor treating GERD, nocturnal GERD, diurnal GERD, or tLESR by implantingan electrical stimulation device and operating the stimulation device tostimulate the patient's LES in a manner that induces within the patienta sense of satiety and a desire to eat food more slowly. Theindividual's satiety sensation with treatment is accelerated whenmeasured against the same individual's sense of satiety in the absenceof any electrical stimulation. Accelerating an individual's sense ofsatiety results in the individual eating less food and thereforedecreases the likelihood of weight gain associated with successful GERDtherapy.

Treatment Methodologies

In one embodiment, any stimulator device, including a macrostimulator ormicrostimulator, can be programmed to implement one or more treatmentprotocols disclosed herein. It should be appreciated that the treatmentmethods described below are implemented in a stimulator, such as amacrostimulator or microstimulator, having a plurality of electrodes, orat least one electrode, including, but not limited to, unipolar orbipolar electrodes, an energy source, such as a battery or capacitor,and a memory, whether local to the stimulator or remote from thestimulator and adapted to transmit data to the stimulator, which storesa plurality of programmatic instructions wherein said instructions, whenexecuted by the macro/microstimulator, execute the stimulationtherapies, as described below.

The present application is directed toward stimulation treatment methodsthat permit a patient, with one or more implanted stimulator systems asdescribed above, to engage in a swallow that causes liquid, food mass,food mass mixed with liquid, or any bolus of matter greater than 1 cc topass through the patient's esophagus (collectively referred to as a wetswallow or bolus swallow; wet swallow and bolus swallow shall be usedinterchangeably) while concurrently having one or more gastrointestinalanatomical structures, such as the upper esophagus, upper esophagealsphincter, esophagus, lower esophageal sphincter, the distal esophagus,the gastric cardia, cardiac sphincter, gastric fundus, and/or the vagusnerve, or any of the other anatomical structures described herein, besubjected to electrical stimulation.

The prior art has conventionally taught that stimulation ofgastrointestinal structures, particularly the esophagus and loweresophageal sphincter, must cease when a patient engages in a swallow. Ithas now been unexpectantly determined that, if stimulated appropriately,such stimulation need not cease during, concurrent with, or in responseto a patient engaging in a wet swallow. The stimulation protocols,described below, are effectuated through the stimulation devicesdescribed herein and by the patent documents incorporated herein byreference. Such devices generally include any device for electricalstimulation of one or more structures in the esophagus and for use inthe treatment of diurnal GERD, comprising a pulse generator providingelectrical stimulation, a power source for powering the pulse generator,one or more stimulating electrodes operatively coupled or connected tothe pulse generator wherein the electrode sets are adapted to bepositioned within or adjacent to one or more anatomical structuresdescribed herein. Preferably, the stimulating electrodes are designed tobe implanted predominantly in the submucosal layer or the muscularislayer of the esophagus. In one embodiment, a plurality of electrodes inelectrical communication with a macrostimulator are implantedpredominantly in the muscularis propria. In one embodiment, a pluralityof electrodes in electrical communication with a microstimulator areimplanted predominantly in the submucosal layer, if done endoscopically,and in the muscularis layer if done laparoscopically.

In one embodiment, the stimulation parameters, which are effectuatedthrough an electrical pulse that can be of any shape, including square,rectangular, sinusoidal or saw-tooth, may comprise any of the variableranges detailed in the table below

TABLE 1 Pulse On Off Pulse Type Pulse Width Frequency Pulse AmplitudeCycle Cycle Short Pulse 1-999 μsec 1-100 Hz Low (1-999 μAmp) 0-24 hrs0-24 hrs Intermediate (1-50 mAmp) and any values therein Intermediate1-250 msec 1-100 Hz Low (1-999 μAmp) 0-24 hrs 0-24 hrs PulseIntermediate (1-50 mAmp) and any values therein Intermediate 1-250 msec1-59 cpm Low (1-999 μAmp) 0-24 hrs 0-24 hrs Pulse Intermediate (1-50mAmp) and any values therein Long Pulse 251 msec-1 sec 1-59 cpm Low(1-999 μAmp) 0-24 hrs 0-24 hrs Intermediate (1-50 mAmp) and any valuestherein

In one embodiment, the present invention is directed to a method fortreating esophageal disease by electrically stimulating a loweresophageal sphincter (LES) or nerve supplying the LES that causesimprovement in the lower esophageal sphincter pressure or functionwithout affecting, preventing, prohibiting, or otherwise hindering abolus swallow induced relaxation of the lower esophageal sphincter orbolus swallow induced esophageal body motility. In this embodiment,because electrical stimulation need not be inhibited, there is no needto sense for the bolus swallow in order to trigger a cessation ofelectrical stimulation and, therefore, a stimulator need not beprogrammed to sense for the bolus swallow, to modify stimulation inresponse to a bolus swallow (even if the stimulation device has sensingcapabilities), or to be otherwise responsive to a bolus swallow.

This stimulation process improves or normalizes lower esophagealsphincter function because it improves lower esophageal sphincterpressure while not prohibiting or preventing a natural bolus swallow.This process also a) does not affect gastric distension inducedrelaxation of the lower esophageal relaxation, b) improves the postbolus swallow augmentation of the LES pressure, and c) improves theesophageal body function, among other therapeutic benefits, as describedabove.

Having eliminated the need to dynamically control the electricalstimulation based on swallow sensing, the system can be allowed toengage in automated “on/off” duty cycles that can range from 1 second to24 hours. During the “on” period, stimulation is preferably applied fora long enough period to enable recruitment of adequate nerves and/ormuscle fibers to achieve the desired pressure, function or effect. Thedesired “on” period is patient specific and is preferably calculatedbased on the time required to change the LES pressure from baselinepressure or function to the desired therapeutic pressure or functionplus additional time to maintain the therapeutic pressure (maintenancetime) or function. In one embodiment, the maintenance time ranges from 1second to 12 hours. While sensors are not required, in one embodiment,the “on” period can be determined, or triggered by, sensors that sensechanges in the LES, such as LES pressure changes, or the esophagus.Those sensing electrodes sense one or more of change in gastrointestinalmuscle tone or impedance, peristaltic activity, esophageal peristalsis,esophageal pH, esophageal pressure, esophageal impedance, esophagealelectrical activity, gastric peristalsis, gastric electrical activity,gastric chemical activity, gastric hormonal activity, gastrictemperature, gastric impedance, electrical activity, gastric pH, bloodchemical and hormonal activity, vagal or other gastrointestinal neuralactivity and salivary chemical activity and can be preferably positionedin or adjacent one or more of the esophagus, the stomach, the smallintestine, the colon, the vagus or other gastrointestinal nerves and thevascular system.

The “off” period is preferably set in order to prevent development oftolerance or muscle fatigue, to improve device functionality, and tooptimize energy consumption from the battery. The desired “off” periodranges from 1 second to 24 hours. The desired “off” period is patientspecific and calculated based on the time required to change the LESpressure or function from the desired therapeutic pressure or functionto the baseline pressure or function plus optional additional time tomaintain the baseline pressure (relaxation time) or function. In oneembodiment, the relaxation time ranges from 1 second to 12 hours. Whilesensors are not required, in one embodiment, the “off” period can bedetermined, or triggered by, sensors that sense changes in the LES, suchas pressure, or the esophagus. Those sensing electrodes sense one ormore of change in gastrointestinal muscle tone or impedance, peristalticactivity, esophageal peristalsis, esophageal pH, esophageal pressure,esophageal impedance, esophageal electrical activity, gastricperistalsis, gastric electrical activity, gastric chemical activity,gastric hormonal activity, gastric temperature, gastric impedance,gastric pH, blood chemical and hormonal activity, vagal or othergastrointestinal neural activity and salivary chemical activity and canbe preferably positioned in or adjacent one or more of the esophagus,the stomach, the small intestine, the colon, the vagus or othergastrointestinal nerves and the vascular system.

Accordingly, in one embodiment, stimulation can be provided for a firstperiod to generate a LES pressure, function or esophageal function of afirst threshold level, then the stimulation can be lowered or removedwhile still maintaining LES pressure, function or esophageal function ator above the first threshold level of LES pressure, function oresophageal function, thereby treating diurnal GERD and othergastrointestinal indications. Stimulation of greater than a firstthreshold level of LES pressure can be delivered within a time period ofless than a first time period, thereby treating certain gastrointestinalindications. In one embodiment, the present specification discloses atreatment method in which stimulation, such as at or under 30 mAmp, 15mAmp, 10 mAmp, 8 mAmp, or any increment therein, is applied to achieve aLES pressure of less than a first threshold level and, concurrently, wetswallows are still enabled without terminating or decreasing thestimulation. In one embodiment, the present specification discloses atreatment method in which stimulation, such as at or under 30 mAmp, 15mAmp, 10 mAmp, 8 mAmp, or any increment therein, is applied and thenterminated, after which LES pressure function or esophageal functionincreases beyond a first threshold level and, concurrently, wet swallowsare still enabled. It should be appreciated that the stimulationparameters can be presented in terms of total energy applied. Forexample, the current stimulation parameters can be replaced, throughoutthis specification, with preferred energy levels, such as at or under 6mC, 3 mC, 1 mC, 0.08 mC, or any increment therein.

It should further be appreciated that the treatment methodologiesdisclosed herein adjust for, take advantage of, account for, orotherwise optimally use a delayed, or latent, pressure response from theLES in response to electrical stimulation. Conventionally, the prior arthas taught that the LES instantaneously responds, either by contractingor relaxing, to the application of, or removal of, electricalstimulation. In the present treatment methodologies, the LES has adelayed or latent response to electrical stimulation, thereby resultingin a gradual increase in LES pressure after the application ofelectrical stimulation and a sustained heightened level of LES pressureafter electrical stimulation is terminated, at least for certainstimulation parameters. Accordingly, a desired normalization of LESpressure or tone can be achieved well in advance of an expected diurnalGERD triggering event, such as eating, sleeping, napping, laying down,being in a supine position, bolus swallowing, or engaging in physicalactivity, by applying electrical stimulation before the diurnal GERDtriggering event and then terminating the stimulation prior to, during,or after the diurnal GERD triggering event. Multiple embodiments of thepresent invention take advantage of this delayed response by stimulatingthe LES in a manner that does not cause immediate contraction of themusculature or an immediate increase in LES pressure. For example, inone embodiment, stimulation is directed to the LES at a level of no morethan 6 mC repeated on a regular basis, for example 20 times a second,for a specific period of time, for example 30 minutes. This results incontraction of the LES and a rise in LES pressure or improvement in LESfunction that does not occur until after the initial 5 minutes ofstimulation and that continues or is maintained once stimulation hasbeen terminated. In one embodiment, stimulation is directed to the LESat a level of no more than 6 mC repeated on a regular basis, for example20 times a second, for a specific period of time, for example 30minutes. This results in contraction of the LES and a rise in LESpressure that does not occur until after the initial stimulationinitiated and that continues or persists once stimulation has beenterminated.

In these stimulation methodologies, a sub-threshold stimulation thatdoes not generate an instantaneous LES or esophageal function responseis applied for a predefined duration of time to achieve a therapeuticresponse. In one embodiment, a sub-threshold stimulation means that anapplied stimulation does not substantially instantaneously achieve acontraction. A sub-threshold stimulation may have stimulation parametersof less than 20 mAmp, less than 10 mAmp, or less than 8 mAmp. In oneembodiment, a threshold or above threshold stimulation means that anapplied stimulation substantially instantaneously achieves a contractionand may have stimulation parameters of greater than 20 mAmp, greaterthan 10 mAmp, or greater than 8 mAmp. Sub-threshold stimulation hasmultiple advantages, including improved device functionality, improvedenergy transfer in a wireless microstimulator, improved patient safety,decreased patient adverse symptoms or side effects, no sensationassociated with stimulation and decreased tolerance and/or fatigue.

Referring to FIG. 1, a normal esophageal pressure profile 100 is shown.With deglutition, the peristaltic wave follows immediately after the UESrelaxation, producing a lumen-occluding contraction of the esophagealcircular muscle. The contraction wave migrates aborally at a speed thatvaries along the esophagus. The peristaltic velocity averages about 3cm/sec in the upper esophagus, then accelerates to about 5 cm/sec in themid-esophagus, and slows again to approximately 2.5 cm/sec distally. Theduration and amplitude of individual pressure waves also varies alongthe esophagus. The duration of the wave is shortest in the proximalesophagus (approximately 2 seconds) and longest distally (approximately5 to 7 seconds). Peak pressures average 53±9 mmHg in the upperesophagus, 35±6 mmHg in the mid-portion, and 70±12 mmHg in the loweresophagus. These parameters can be influenced by a number of variablesincluding bolus size, viscosity, patient position (e.g., upright vs.supine), and bolus temperature. For instance, a large bolus elicitsstronger peristaltic contractions that migrate distally at a slower ratethan a small bolus. The peristaltic velocity is also slowed by outflowobstruction or increases in intra-abdominal pressure. Warm boluses tendto enhance, whereas cold boluses inhibit the amplitude of peristalticcontractions.

Accordingly, bolus 102 propagates through the UES 112, esophageal body115, and LES 117 over a period of approximately, and typically, tenseconds. As the bolus 102 moves through, portions of the UES 112,esophageal body 115, and LES 117 experience an increase in pressure. Ina normal person, the baseline pressure range for the UES 112 is between34 and 104 mmHg, for the esophagus 115 is between 30 and 180 mmHg, andfor the LES 117 is between 10 and 45 mmHg. At the point of LESrelaxation 110, which occurs to permit the bolus to pass through intothe stomach, the LES pressure decreases to below approximately 8.4 mmHg.Notably, in a normal patient, post-swallow, the LES pressure increases,after having decreased for the swallow, and then remains at a higherbaseline pressure level than just immediately prior to the swallow.

In one embodiment, the presently disclosed methods and systems return anabnormally functioning LES to a state of improved function or normalcy,post-stimulation or post initiation of stimulation. The treatmentmethodology comprises implanting a stimulation device, as describedherein, and electrically stimulating the device to cause an increasedLES pressure, in accordance with any of the stimulation methodologiesdescribed herein. After stimulation is terminated, one or more of thefollowing functional parameters, characteristic of an abnormallyfunctioning LES, achieves normal physiological range: a) LES basalpressure (respiratory minima) returns to a range of 15-32 mmHg, b) LESbasal pressure (respiratory mean) returns to a range of 10-43 mmHg, c)LES residual pressure returns to a range of less than 15 mmHg, d) LESpercent relaxation returns to a range of greater than 40%, e) LESduration of contraction returns to a range of 2.9 seconds to 5.1 seconds(3 cm above the LES), 3 seconds to 5 seconds (8 cm above the LES), or2.8 seconds to 4.2 seconds (13 cm above the LES), f) lower esophagealacid exposure during 24-hour pH-metry returns to a range of pH<4 forless than 10%, and preferably less than 5%, of total or less than 8% orpreferably less than 3% of supine time, and/or g) esophageal refluxevents return to less than 100 per 24 hour period or reduce by 50% asdocumented by impedance pH monitoring, i) normal LES compliance, j)normal bolus swallows return with complete bolus transit, defined asdetection of bolus exit in all 3 of the distal impedance channels and/ork) esophageal pH returns to a range equal to twice the normal, asdefined in the table below or any normative standards for the measuringdevice.

TABLE 2 Catheter-based dual-probe (distal and proximal) esophageal pHmonitoring Variable Normal Time pH <4.0 (%) Proximal (%) Distal (%)Total period <0.9 <4.2 Upright period <1.2 <6.3 Recumbent period <0.0<1.2 Distal = 5 cm above manometric defined proximal border of the LES.Proximal = 20 cm above manometric defined proximal border of the LES.Catheter free distal esophageal pH monitoring Variable Normal Time pH<4.0 (%) Distal (%) Total period <5.3 Upright period <6.9 Recumbentperiod <6.7 Distal = 6 cm above endoscopic defined gastroesophagealjunction

Accordingly, the presently disclosed methods and systems modify one ormore of the aforementioned functional parameters characteristic of anabnormally functioning LES or the esophagus to that of a normally orimproved functioning LES or the esophagus, even after stimulation isterminated. By transforming an abnormally functioning LES or theesophagus to a normally or improved functioning LES or the esophagus,esophageal reflux, diurnal GERD, esophageal motility disorders oresophageal neural, muscular or neuromuscular disorders, can beeffectively treated.

In another embodiment, the presently disclosed methods and systemsmodify an abnormally functioning LES or the esophagus to provide for anadequately functioning LES or the esophagus post-stimulation. Thetreatment methodology comprises implanting a stimulation device, asdescribed herein, and electrically stimulating the tissue to cause anincrease in LES pressure or improvement in LES function, in accordancewith any of the stimulation methodologies described herein. Afterstimulation is terminated, one or more of the following functionalparameters, characteristic of an abnormally functioning LES, returns toa physiological range sufficient to prevent esophageal reflux, diurnalGERD, esophageal motility disorders or esophageal neural, muscular orneuromuscular disorders: a) LES basal pressure, b) LES residualpressure, c) LES percent relaxation, d) LES duration of contraction, e)distal esophageal pH, f) esophageal reflux events, g) esophageal bodyfunction, h) LES compliance and i) esophageal perception or sensation.Accordingly, the present invention modifies physiological parameterscharacteristic of an abnormally functioning LES or esophagus, relativeto the patient's pre-treatment state, to that of an adequatelyfunctioning LES or esophagus, even after stimulation is terminated. Bytransforming an abnormally functioning LES to an adequately functioningLES, esophageal reflux, diurnal GERD, esophageal motility disorders oresophageal neural, muscular or neuromuscular disorders can beeffectively mitigated.

In another embodiment, the present invention improves the LES pressureprofile of an abnormally functioning LES post-stimulation. The treatmentmethodology comprises implanting a stimulation device, as describedherein, and electrically stimulating the tissue to cause an increase inLES pressure, in accordance with any of the stimulation methodologiesdescribed herein. After stimulation is terminated, LES basal pressure orfunction is improved, relative to the patient's pre-treatment state, byat least 5%, preferably 10%. Accordingly, the presently disclosedmethods and systems modify the pressure profile of an abnormalfunctioning LES, even after stimulation is terminated. By doing so,esophageal reflux, diurnal GERD, esophageal motility disorders oresophageal neural, muscular or neuromuscular disorders can beeffectively mitigated.

In another embodiment, the presently disclosed methods and systemsimprove, post-stimulation, at least one of a) esophageal body pressure,b) esophageal body contractility, c) esophageal body motility, d)esophageal body bolus transit, or e) esophageal body peristalsis,resulting in improved esophageal acid clearance after a reflux event,decreasing esophageal acid exposure time, decreasing proximate extent ofreflux, and minimizing damage from exposure of esophageal mucosa togastro-duodenal refluxate. The treatment methodology comprisesimplanting a stimulation device, as described herein, and electricallystimulating the tissue to cause an increase in LES pressure, inaccordance with any of the stimulation methodologies described herein.After stimulation is terminated, at least one of a) esophageal bodypressure, b) esophageal body contractility, c) esophageal body motility,e) esophageal body bolus transit, or f) esophageal body peristalsisimproves and remains in an improved state while the stimulator is off.

In another embodiment, the presently disclosed methods and devicesachieve any of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the patient's esophagushas a function, and treating the patient by applying electricalstimulation, wherein the stimulation causes an improvement in esophagealfunction. Esophageal function may include any one of esophagealpressure, bolus transit, esophageal perception, esophagealaccommodation, esophageal clearance of the refluxate or esophagealcompliance.

In another embodiment, the presently disclosed methods and devicesachieve any of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the patient's esophagushas a function, and treating the patient by applying electricalstimulation, wherein the stimulation causes a non-instantaneous ordelayed improvement in esophageal function. Esophageal function mayinclude any one of esophageal pressure, bolus transit, esophagealperception, esophageal accommodation, esophageal clearance of therefluxate or esophageal compliance.

In one embodiment, in a patient with a hiatal hernia, the presentlydisclosed method and device achieve any of the aforementionedtherapeutic objectives by fixing the hiatal hernia by any methodfollowed by implanting a stimulation device adapted to be implantedwithin the patient's lower esophageal sphincter, wherein the patient'sLES or esophagus has a function, and treating the patient by applyingelectrical stimulation, wherein the stimulation causes anon-instantaneous or delayed improvement in LES or esophageal function.LES function may include one of LES basal pressure, LES residualpressure, LES percent relaxation, LES duration of contraction, distalesophageal pH, esophageal reflux events and LES compliance. Esophagealfunction may include any one of esophageal pressure, bolus transit,esophageal perception, esophageal accommodation, esophageal clearance ofthe refluxate or esophageal compliance.

In another embodiment, in a patient with a foreshortened esophagus or anLES above the diaphragm, the presently disclosed method and deviceachieve any of the aforementioned therapeutic objectives by creating apredefined length of abdominal esophagus or by bringing the LES belowthe diaphragm by any method followed by implanting a stimulation deviceadapted to be implanted within the patient's lower esophageal sphincter,wherein the patient's LES or esophagus has a function, and treating thepatient by applying electrical stimulation, wherein the stimulationcauses a non-instantaneous or delayed improvement in LES or esophagealfunction. LES function may include one of LES basal pressure, LESresidual pressure, LES percent relaxation, LES duration of contraction,distal esophageal pH, esophageal reflux events and LES compliance.Esophageal function may include any one of esophageal pressure, bolustransit, esophageal perception, esophageal accommodation, esophagealclearance of the refluxate or esophageal compliance.

In another embodiment, in a patient with a disrupted or wideneddiaphragmatic hiatus, the presently disclosed method and device achieveany of the aforementioned therapeutic objectives by fixing or narrowingthe hiatus by any method followed by implanting a stimulation deviceadapted to be implanted within the patient's lower esophageal sphincter,wherein the patient's LES or esophagus has a function, and treating thepatient by applying electrical stimulation, wherein the stimulationcauses a non-instantaneous or delayed improvement in LES or esophagealfunction. LES function may include one of LES basal pressure, LESresidual pressure, LES percent relaxation, LES duration of contraction,distal esophageal pH, esophageal reflux events and LES compliance.Esophageal function may include any one of esophageal pressure, bolustransit, esophageal perception, esophageal accommodation, esophagealclearance of the refluxate or esophageal compliance.

Referring to FIG. 2, in a typical diurnal GERD patient, the LES relaxesprior to swallow 205. Post-swallow, the LES increases pressure 210,which can be observed for a short duration following the swallow, andthen reverts to a resting tone 215. It should be appreciated, however,that the resting tone 215 is too low to prevent reflux. Referring toFIG. 3, the resting tone 315, both before and after the relaxation 310associated with a bolus swallow, is significantly increased using thedevices and methodologies of the present invention, while still keepingintact the relaxation function 310. This represents a significantimprovement over treatments that closed the LES and did not allow themuscle to properly relax during swallows, absent termination ofstimulation.

Referring to FIGS. 4-7, the presently disclosed methods and systemsenable different post-stimulation residual effects, including anincrease in LES pressure post-stimulation 410 followed by a decrease inLES pressure down to a stimulation state 405 over a period of 2 to 3hours (FIG. 4), a slow decrease in LES pressure post-stimulation 510back to a pre-stimulation LES pressure level 505 over a period of 1 to 2hours (FIG. 5), a continued increase in LES pressure post-stimulation610 followed by a decrease in LES pressure which still remains above apre-stimulation state 605 after a period of 2 to 3 hours (FIG. 6), andminimal to no increase in LES pressure during stimulation 705 and acontinued increase in LES pressure post-stimulation 710 followed by adecrease in LES pressure which still remains above a pre-stimulationstate after a period of 2 to 3 hours (FIG. 7).

Accordingly, in one embodiment, the present invention encompasses amethod for controlling muscle action using electrical stimulation by amodulated electrical signal having carrier frequency in the range of 2KHz-100 KHz and an on-off modulating signal having an “on” duration inthe range of 5 μs to 500 msec and, in particular, 200 μs.

In one embodiment, a pacemaker lead, such as a modified Medtronic 6416200 cm, is secured to the LES in a submucosal tunnel using endoclipsalong the body of the lead and exteriorized nasally. Stimulation isapplied using a 200 μsec to 3 msec pulse with a pulse amplitude of 1mAmp to 15 mAmp, more preferably 5 mAmp to 10 mAmp, pulse frequency ofpreferably less than 1 msec, more preferably 200 μs, and a pulse widthof 200 μsec. The patient's resting LES pressure, which is greater thanor equal to 5 mmHg, is thereafter increased by at least 5%, morepreferably 25-50%. Additionally, transient LES relaxation is improved byat least 5%, LES function is improved by at least 5%, esophageal bodypressure is improved by at least 5%, esophageal body function isimproved by at least 5%, symptoms of diurnal GERD are improved by atleast 5%, esophageal acid exposure is improved by at least 5%, qualityof life is improved by at least 5%, caloric intake is improved by atleast 5%, and/or weight is improved by at least 5%.

These improvements are achieved without any adverse effect on patient'sswallow function, adverse symptoms, or cardiac rhythm disturbances.These improvements are also achieved by avoiding continuous electricalstimulation, which yields problems of muscle fatigue, build up oftolerance, tissue damage, and excessively high requirements for localenergy storage, such as capacitor size or battery life.

In another embodiment, the stimulator may be operated using a pulsehaving a frequency of 20 Hz (1-100 Hz), a pulse amplitude of 1 μAmp-1Amp, more preferably 1-20 mAmp, and a pulse width of 1 μsec-1 msec, andmore preferably 100-500 μsec. The stimulator may also be stimulatedusing a pulse having a frequency of 20 Hz (1-100 Hz), a pulse amplitudeof 1-20 mA (1 μAmp-1 Amp), and a pulse width of 1-50 msec (500 μsec-100msec). The stimulator may also be stimulated using a pulse having afrequency of 5 cpm (1-100 cpm), a pulse amplitude of 1-20 mAmp (1 μAmp-1Amp), and a pulse width of 100-500 msec (1 msec-1 sec).

In certain applications, there is an advantage to combining neuralstimulation with direct muscle stimulation. Such applications include,for example, gastric stimulation for gastroparesis where a combinedeffect on gastric muscle and neural modulation can be synergistic inimproving both gastric emptying rates and symptoms associated withgastroparesis. Another example can be the treatment of chronic refluxdisease where both high frequency and low frequency pulses can havedesirable effects on maintaining adequate lower esophageal sphinctertone or function while modulating the perception of symptoms associatedwith diurnal GERD.

In certain applications where an implantable electrode or a leadlessdevice is used for delivering electrical stimulation, it is technicallymore feasible to apply lower pulse width (having higher frequencycomponents) than signals having wider pulse duration. The reason is thatirreversible electrochemical effects occur when the total chargetransfer through the electrode-tissue interface at any given timeincreases above a certain threshold. In these cases electrolysis occurswhich releases metal ions into the tissue, damages the electrode, andcauses dangerous pH changes in the local tissue. This has negativeeffects on the electrode longevity and on the tissue and should beavoided especially in chronic applications where stimulation of the samesite using the same electrode or device is planned for an extendedperiod of time.

Some methods for overcoming the problems of using long pulse durationswere developed that attempt to enhance the capacitance of theelectrode-tissue interface so as to increase the threshold forirreversible effects thereby increasing the maximal pulse width that canbe used chronically. Electrode capacitance can be increased in variousways, such as by enhancing effective electrode surface area by coating(e.g. coating with iridium-oxide or titanium nitride), by changing theelectrode material, and/or by geometrical changes in the electrodeshape. These methods, however, have some undesirable consequences, suchas a significant increase in the manufacturing cost of the electrodeand/or making the electrode unsuitable for specific implantationprocedures. It is therefore useful to minimize the use of long pulsedurations.

Furthermore, it should be noted that the use of square wave pulses,which is very common in conventional electrical stimulation systems,contains energy in frequency bands that are higher than the base rate ofthe pulse width. In general, when a square wave is used then most of theenergy is delivered in the base rate and a portion of the energy isdelivered in frequencies that are multiples (harmonics) of such baserate. Consequently, when a wide pulse width is delivered at a lowfrequency rate, some energy is also delivered in higher bands (multiplesof the base rate) and also multiples of the reciprocal value of thepulse width. The practical effect, however, of these higher frequencycomponents (or harmonics) is relatively small since only a small portionof the energy is delivered in these bands. It should further beappreciated that some frequencies, especially very high ones, are notabsorbed in most tissues and can therefore be used as carriers to lowerfrequency signals that modulate them. Accordingly, high frequencies canbe used to transfer or carry energy to the tissue without anyphysiological effect. Recovery of the low frequency signal is performedusing a demodulator.

In light of the above, in one embodiment, a combination of low and highfrequency signals (e.g. a waveform including both a high frequencycomponent and a low frequency component) are delivered through anelectrode or a leadless stimulating device with the purpose of applyingtwo separate effects to the stimulated tissue and positively impactinglower esophageal sphincter tone. The low frequency signal will bemodulated on a high frequency carrier known to be neutral to muscle tonewhereas the low frequency signal will be demodulated by the tissueitself and deliver a separate impact on the tissue, which is known tooccur with a direct muscle stimulation using low frequency signals. Thesignal is designed to have a zero net charge delivered to the tissueover durations shorter than 1 ms thereby allowing flexibility inelectrode design far more than what would be required if using a longpulse duration directly.

In one embodiment, referring to FIG. 8, the modulation is achieved bypulse trains having a base high frequency and duration equal to thedesired long pulse width. Here, the stimulation train does not have anet zero charge; therefore, in order to discharge the electrode-tissuecapacitance, a 350 msec time period can be deployed, using a lowimpedance pathway switched by the stimulation device. Alternatively, asingle negative discharging pulse can be applied once every 700 mseccycle. The low impedance connection can also preferably be appliedfollowing each of the 100 μsec pulses thereby minimizing the maximal netcharge accumulated on the electrode-tissue capacitance. There areseveral advantages of this waveform configuration: 1) the longest pulseduration applied is 100 μsec thereby relaxing the demands on achronically implantable electrode capacitance that would have beenrequired for a 350 msec pulse duration; 2) a train duration of 350 msecadds a low frequency component which is known to have a direct positiveeffect on muscle tone; 3) there is a reduced energy requirement from thedevice, resulting from the lower total pulse durations; and 4) the totalstimulation result is optimized by a combination of two differentfrequency bands, each controlling the muscle through an independentphysiological mechanism.

In another embodiment, the present invention encompasses an apparatuscomprising a housing, pulse generator capable of generating square wavesin the frequency range of 2 KHz-100 KHz, conductive tissue interface,means for fixation of conductive tissue interface to muscle tissue,programmable control unit capable of delivering said pulse generatoroutput to the tissue intermittently whereas each “on” duration can beprogrammable in the range of 5 μsec to 500 msec and an “off” durationprogrammable in the same or different range. Optionally, the muscletissue is the LES, esophagus, or UES. Optionally, the carrier frequencyis in the range of 40 KHz-60 KHz and “on” duration is 300-400 msec.Optionally, the signal structure may be triggered by other timingmechanisms, including various patient-specific attributes, activities,and states. Optionally, a control unit, which is separate from amicrostimulation device, includes a demodulator and a pulse generatorfor the high frequency carrier, transmits energy to the microstimulatorto power the pulse generator, and includes modulation information usinga different carrier frequency. Optionally, the stimulation devicecomprises multiple leads output and alternates a modulation signalbetween two or more stimulation locations where, while one location hasan “on” state, the other location has an “off” state, and vice-versa.

In another embodiment, the stimulator may be stimulated using an “on”phase and an “off” phase, wherein the on phase is between 1 minute and 1hour and the off phase is between 1 minute and 1 hour. Preferably, boththe on and off phases are between 5 and 30 minutes. In anotherembodiment, the stimulator or microstimulator may be stimulated using acombination of a low frequency pulse and an intermediate or highfrequency pulse. In one embodiment, the low frequency pulses aredelivered for a duration that is 1% to 1000% of the intermediate or highpulse duration.

In another embodiment, the stimulator may be stimulated using an “on”phase and an “off” phase, wherein the on phase is between 1 second and24 hours and the off phase is between 1 second and 24 hours. Preferably,the off phase is longer than the on phase. In this embodiment, thestimulator or microstimulator may be stimulated using a combination of alow frequency pulse and an intermediate or high frequency pulse. In oneembodiment, the low frequency pulses are delivered for a duration thatis 1% to 1000% of the intermediate or high pulse duration. In anotherembodiment a combination of same frequency pulse with varying amplitudecan be used. For example a patient can receive intermittent orcontinuous stimulation at a lower amplitude with one or more session ofstimulation at a higher amplitude where the high amplitude is at leasttwice the low amplitude.

It should be appreciated that, wherever stimulation parameters aredescribed, the stimulation may be initiated by “ramping up” to thestated stimulation levels or may be terminated by “ramping down” to anoff state. The ramp up and ramp down can be as slow or as fast asrequired to effectuate the required therapy.

In one embodiment, the programmed duty cycle, pulse frequency, pulsewidth, pulse amplitude of the stimulator and corresponding electrodeconfiguration are configured to trigger secretion of neurokinin A (NKA)or a similar peptide. The configuration of the frequency and amplitudeis set to efficiently achieve a clinically significant secretion withminimal energy. The session duration can make use of the longdegradation time of NKA and be configured to turn off stimulationfollowing the expected accumulation of sufficient NKA secretion.Electrode configuration, as further described below, can be adapted sothat the desired optimal session duration will alternate in differentregions using implantation of electrodes in different regions of theLES. The configuration of the stimulation to impact local NKA level canbe designed to achieve the required pressure curve as described in FIGS.4-7.

It should further be noted that, because the stimulation device enablesthe therapeutically effective treatment of a plurality of ailments, asdescribed above, at currents below 15 mAmp, one can avoid subjecting thepatient to physical pain, sensation, or discomfort. The present systemcan achieve the therapeutic goals and effectively operate by deliveringlower stimulation levels for longer periods of time, such as bydelivering 3 mAmp for 10 minutes rather than 15 mAmp for 5 minutes. Thepulse frequency can be 20 Hz and the stimulation can be delivered lessthan five times per day, such as three times per day.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device, such as a macrostimulator ormicrostimulator, adapted to be implanted within the patient's loweresophageal sphincter and adapted to apply electrical stimulation to thepatient's lower esophageal sphincter; and programming, using, oroperating said stimulation device, wherein said programming, use, oroperation defines, uses, or is dependent upon a plurality of stimulationparameters that determine the application of electrical stimulation tothe patient's lower esophageal sphincter and wherein said stimulationparameters are selected, derived, obtained, calculated, or determined,at least in part, to account for a latent, delayed, time-delayed, orfuture response of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and to apply electrical stimulationto the patient's lower esophageal sphincter, wherein said loweresophageal sphincter exhibits a latent, delayed, time-delayed, or futureresponse to applied electrical stimulation; and treating said patient byapplying electrical stimulation based upon derived from, or dependentupon said latent, delayed, time-delayed or future response.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and to apply electrical stimulationto the patient's lower esophageal sphincter; and initiating, activating,beginning, or starting said electrical stimulation prior to apre-defined or fixed time wherein said pre-defined or fixed time isassociated with a diurnal GERD triggering event and wherein saidinitiation occurs prior to said pre-defined or fixed time by a minimumperiod, such as at least 5 minutes, 10 minutes, 15 minutes, 30 minutes,1 hour, 2 hours, 3 hours, 12 hours, 24 hours, or any time incrementtherein.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and adapted to apply electricalstimulation to the patient's lower esophageal sphincter; and initiating,activating, beginning, or starting said electrical stimulation prior toa pre-defined or fixed time wherein said pre-defined or fixed time isassociated with a diurnal GERD triggering event and wherein saidinitiation occurs prior to said pre-defined or fixed time by a minimumperiod, such as at least 5 minutes, 10 minutes, 15 minutes, 30 minutes,1 hour, 2 hours, 3 hours, 12 hours, 24 hours, or any time incrementtherein; and terminating said electrical stimulation after saidpre-defined or fixed time has passed.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter and adapted to apply electricalstimulation to the patient's lower esophageal sphincter; andprogramming, using, or operating said stimulation device, wherein saidprogramming, use, or operation defines, uses, or is dependent upon aplurality of stimulation parameters that determine the application ofelectrical stimulation to the patient's lower esophageal sphincter andwherein said stimulation parameters are selected, derived, obtained,calculated, or determined, at least in part, to treat diurnal GERDwithout inhibiting, hindering, stopping, or preventing the patient fromswallowing.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation while the patient swallows, duringperiods of esophageal motility, or during esophageal peristalsis.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation in accordance with a preset period andwherein said preset period is not dependent upon, influenced by,modified by, lengthened by, or shortened by a physiological state of apatient.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation in accordance with a preset period andwherein said preset period is not dependent upon, influenced by,modified by, lengthened by, or shortened by the patient swallowing,esophageal motility, esophageal peristalsis, or being in a feedingstate.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation that is not dependent upon, influencedby, modified by, lengthened by, or shortened by a physiological state,biological parameter, sensed physiological or biological parameters of apatient.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter; and treating said patient byapplying electrical stimulation that is not dependent upon, influencedby, modified by, lengthened by, or shortened by the patient swallowing,esophageal motility, esophageal peristalsis, or being in a feedingstate.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingsufficient electrical stimulation to increase said pressure but not toinhibit, hinder, stop, or prevent swallowing, esophageal motility,esophageal peristalsis, or being in a feeding state.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the lower esophagealsphincter has a function, and treating the patient by applyingsufficient electrical stimulation to improve the function but not toinhibit, hinder, stop, or prevent swallowing, esophageal motility, oresophageal peristalsis or dissuade a patient from being in a feedingstate.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes an increase insaid pressure of at least 5% only after an elapsed period of time of atleast one minute.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation improves or normalizeslower esophageal function, improves or normalizes LES pressure, orincreases LES pressure to a normal physiological range only after anelapsed period of time or only after a delay of at least one minute.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes anon-instantaneous or delayed increase in said pressure.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein the lower esophagealsphincter has a function, and treating the patient by applyingelectrical stimulation, wherein the stimulation causes anon-instantaneous or delayed improvement in the function.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes anon-instantaneous or delayed increase in said pressure and wherein saidnon-instantaneous or delayed increase in the pressure normalizes LESfunction, normalizes LES pressure, increases LES pressure to a normalphysiological range, or increases LES pressure by at least 3%.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes a gradualincrease in said pressure.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation, wherein said stimulation causes an increase insaid pressure after said electrical stimulation is terminated.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, wherein said lower esophagealsphincter has a pressure; and treating said patient by applyingelectrical stimulation having a first level, wherein said stimulationcauses an increase in said pressure after said electrical stimulation isdecreased from said first level.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by improving thepressure or function of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives, wherein said patienthas a lower esophageal sphincter and wherein said lower esophagealsphincter has a pressure, by increasing the pressure of the patient'slower esophageal sphincter through the application of electricalstimulation to the lower esophageal sphincter or areas proximatethereto.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives, wherein said patienthas a lower esophageal sphincter and wherein said lower esophagealsphincter has a pressure, by increasing the pressure of the patient'slower esophageal sphincter through the application of electricalstimulation to the lower esophageal sphincter or areas proximatethereto, and wherein said pressure does not inhibit or otherwise hinderthe patient's ability to swallow.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter throughthe application of electrical stimulation to the lower esophagealsphincter or areas proximate thereto.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by modifying thepressure or function of the patient's lower esophageal sphincter throughthe application of electrical stimulation to the lower esophagealsphincter or areas proximate thereto and wherein said pressure does notinhibit or otherwise hinder the patient's ability to swallow.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation in accordance with at least one onperiod, wherein said on period is between 1 second and 24 hours and isnot triggered by, substantially concurrent to, or substantiallysimultaneous with an incidence of acid reflux, and at least one offperiod, wherein said off period is greater than 1 second.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation, wherein a pulse amplitude from a singleelectrode pair ranges from greater than or equal to 1 mAmp to less thanor equal to 8 mAmp.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse duration of approximately200 μsec.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse duration of approximately1 msec.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse energy level of <10 mAmp,pulse duration of <1 second, and/or pulse frequency of <50 Hz.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation having a pulse energy level of 1 mAmp to10 mAmp (preferably 1 mAmp), pulse duration in a range of 50 μsec to 1msec (preferably 215 μsec), a pulse frequency of 5 Hz to 50 Hz(preferably 20 Hz), pulse on time in a range of 10 minutes to 120minutes (preferably 30 minutes), and/or pulse off time in a range of 10minutes to 24 hours.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation to increase LES pressure above abaseline or threshold LES pressure, wherein said LES pressure remainsabove said baseline or threshold LES pressure after termination ofelectrical stimulation.

In one embodiment, the presently disclosed methods and devices achieveany of the aforementioned therapeutic objectives by providing orimplanting a stimulation device adapted to be implanted within thepatient's lower esophageal sphincter, and treating said patient byapplying electrical stimulation to increase LES tone above a thresholdLES tone, wherein said LES tone remains above said threshold LES toneafter termination of electrical stimulation.

In one embodiment, the presently disclosed methods and devices provide amacrostimulator programmed, adapted to, or configured to perform any ofthe aforementioned methods or treatment protocols.

In one embodiment, the presently disclosed methods and devices provide amacrostimulator comprising at least one electrode, an energy source, anda pulse generator in electrical communication with the at least oneelectrode and energy source, wherein said pulse generator is programmed,adapted to, or configured to perform any of the aforementioned methodsor treatment protocols.

In one embodiment, the presently disclosed methods and devices provide amicrostimulator programmed, adapted to, or configured to perform any ofthe aforementioned methods or treatment protocols.

In one embodiment, the presently disclosed methods and devices provide amicrostimulator comprising at least one electrode, an energy source, anda pulse generator in electrical communication with the at least oneelectrode and energy source, wherein said pulse generator is programmed,adapted to, or configured to perform any of the aforementioned methodsor treatment protocols.

Such treatment methods may be combined, directed toward any of theaforementioned therapeutic objectives, and/or implemented throughstimulating any of the aforementioned anatomical areas. The treatmentmethods may be further modified by using specific stimulationparameters, open loop data processes, closed loop data processes, thepatient's physical position and degree of activity, the patient's eatingstate, timing, quantity or content thereof, certain physiologicalparameters sensed by the device, including LES pressure, oranti-habituation methods to prevent anatomical habituation to a specificset of stimulation parameters. Additionally, because the device canoperate on a time-based schedule, not necessarily physiological triggers(although a physiological trigger can be an optional embodiment),stimulation schedules can be tailored to user behavior and/or routine.For example, stimulation therapy can be delivered or stimulation energycan be transmitted at times that are most convenient, least disruptiveto the patient's activities of daily living, such as only schedulingstimulation while the patient is sleeping, relaxing, or watching TV andscheduling stimulation only after mealtimes. Such additional embodimentsare described below.

Open Loop Programming

In one optional embodiment, the stimulation parameters, including pulsewidth, pulse frequency, pulse amplitude, ramp rates, and/or duty cycle,can be modified by a physician using data sensed by, stored within, ortransmitted from the stimulation device, data sensed by, stored within,or transmitted from a sensor implanted in the patient, and/or datacaptured by an external computing device used by a patient. A stimulatordevice having a local memory, or a transmitter capable of communicatingsensed information to a remotely located memory or memory external tothe patient, captures a plurality of sensed data, as discussed ingreater detail below. Concurrently, a patient controlled computingdevice, such as a laptop, personal computer, mobile device, or tabletcomputer, which is external to the patient is used by the patient tostore data input by the patient relevant to evaluating, monitoring, andadjusting the operation of the stimulator. Both the stimulator captureddata and patient inputted data is then transmitted to a physiciancontrolled device, as described below, to enable the physician toproperly evaluate, monitor, and modify the stimulation parameters.

In one embodiment, the patient-controlled computing device comprises aplurality of programmatic instructions that, when executed, generate adisplay which prompts a user for, and is capable of receiving input fromthe user, information regarding the user's food intake, the timing ofsuch food intake, exercise regimen, degree and extent of physicalsymptoms, incidents of acid reflux, when the user sleeps, when the userlays down, type of food being consumed, quantity of food, among othervariables. This data can be captured and stored locally and/ortransmitted to a remote server for access by a physician. If accessedremotely by a physician, the physician can transmit alerts back to thepatient, via a network in communication with the computing device orconventional communication systems, such as email, text messaging orphone, to confirm dose amounts, patient state information, or providefor therapy adjustment.

In one embodiment, the stimulator captured data includes whatstimulation parameters were used and when, the sensed LES pressureprofile, including the percentage or amount of time the LES pressure wasbelow a certain threshold level, such as 10 mmHg, or above a 2^(nd)threshold level, such as 20 mm Hg, the occurrence of t-LESRs, esophagealpH, supine events, degree of physical movement, among other variables.

The patient-inputted data, when combined with the stimulator captureddata, can provide a holistic view of the patient's condition and theefficacy of a stimulation regimen. In particular, as patient symptomsare mapped to stimulation parameters and analyzed in relation to food ordrink intake, sleep, and exercise regimens, a physician will be able todetermine how best to modify the stimulation parameters, including dutycycle, stimulation initiation times or triggers, stimulation terminationtimes or triggers, pulse width, pulse amplitude, duty cycle, ramp rates,or pulse frequency, to improve patient treatment. As further discussedbelow, the physician will receive both the patient-captured andstimulation device captured data into a diagnostic terminal that can beused to process the information and transmit new stimulation parameters,if necessary, to the stimulation device. For example, the physician canmodify the stimulation parameters in a manner that would lower theincidents of reported acid reflux, generalized pain, pain whileswallowing, generalized discomfort, discomfort while swallowing, or lackof comfort during sleeping or physical exercise. The physician can alsomodify the stimulation parameters, including the initiation andtermination of stimulation, to better match one or more diurnal GERDtriggering events, such as eating, sleeping, lying down, or engaging inphysical activity. The physician can also modify the stimulationparameters, including the initiation and termination of stimulation, tobetter match the patient's personal work or vacation schedule.

Additionally, alerts can be created that can be either programmed intothe patient-controlled device or stimulation device which serve tonotify the patient of a device malfunction, a recommendation to take adrug, a recommendation to come back for a checkup, among othervariables. Those alerts can also be transmitted, via a computingnetwork, to the physician. Furthermore, external data sources, such asdemographic data or expert protocols, can be integrated into thephysician system to help the physician improve the diagnostic andevaluation process and optimize the programmed set of stimulationparameters.

It should further be appreciated that, as the patient controlled deviceand stimulator device accumulate data that maps the therapeutic regimenagainst the patient's activities and symptoms, the patient controlleddevice will be able to determine, and therefore inform the patient of,patterns which tend to increase or decrease the incidents of diurnalGERD, including types of food, quantity of food, timing of eating, amongother variables.

Closed Loop Programming

In one optional embodiment, the stimulation parameters, including pulsewidth, pulse frequency, pulse amplitude, initiation of stimulation,triggers for stimulation, termination of stimulation, triggers toterminate stimulation, ramp rates, and/or duty cycle, can be dynamicallyand intelligently modified by the stimulation device using data sensedby, stored within, or transmitted from the stimulation device, datasensed by, stored within, or transmitted from a sensor implanted in thepatient, and/or data captured by, stored within, and/or transmitted froman external computing device used by a patient.

As discussed above, data maybe captured by a patient-controlled deviceand/or the stimulator device. In this embodiment, a stimulator isfurther programmed to intelligently modify stimulation parameters,without physician input, based upon sensed data and/or patient inputs.In one embodiment, a stimulator determines that LES pressure or functionfails to improve above a predefined threshold, even after a predefinedamount of stimulation, and, accordingly, automatically modifies thestimulation parameters, within a preset range of operation, to yield animprovement in LES pressure increase. In one embodiment, a stimulatordetermines that LES pressure or function improves significantly above apredefined threshold, after a predefined amount of stimulation, ormaintains a level above a predefined threshold and, accordingly,automatically modifies the stimulation parameters, within a preset rangeof operation, to yield an improvement in LES pressure levels orfunction.

In one embodiment, a stimulator determines the LES pressure levelsremain above a predefined threshold level for a sufficient amount oftime such that a subsequent pre-programmed stimulation session orsessions can be postponed or cancelled. In one embodiment, a stimulatordevice monitors LES pressure and initiates stimulation only when LESpressure falls below a predetermined threshold. Preprogrammedstimulation may be modified in order to continue or increase in energy,duration, or frequency until LES pressure rises above a predeterminedthreshold. The LES pressure threshold may be dynamically modified basedupon sensed data.

In one embodiment, a stimulator determines that esophageal pH isindicative of incidents of acid reflux above a predefined thresholdlevel, and, accordingly, automatically modifies the stimulationparameters, within a preset range of operation, to yield an improvementin LES pressure increase to lower such incidents. In one embodiment, astimulator receives a communication from an external patient controlleddevice indicating that the patient is reporting a number of adverseincidents above a predefined threshold, such as acid reflux, generalizedpain, pain while swallowing, generalized discomfort, discomfort whileswallowing, lack of comfort when sleeping, etc. and, accordingly,automatically modifies the stimulation parameters, within a preset rangeof operation, to yield a lower level of such incidents. In oneembodiment, a stimulator receives a communication from an externalpatient controlled device detailing a schedule of potentially diurnalGERD triggering events, including sleep times, eating times, or exercisetimes, and, accordingly, automatically modifies the stimulationparameters, within a preset range of operation, to properly account forsuch diurnal GERD triggering events.

In one embodiment, the stimulator operates using both open loop andclosed loop programming. Stimulation parameters may be established usingopen loop programming methods, as described above, and then modifiedthrough the aforementioned closed loop programming methods. Stimulationparameters may also be established using closed loop programmingmethods, as described above, and then modified through theaforementioned open loop programming methods.

Stimulation Modification Based on Sensed Data

It should be appreciated that the stimulation device may stimulate basedon a plurality of data, including based on LES pressure registeringbelow a predefined threshold, based on a patient's pH level, based onthe patient's physical orientation, based on the patient's meal intake,or based on a predefined time period, among other triggers. It shouldalso be appreciated that the controller may initiate or stop astimulation based on a plurality of triggers, including based on the LESpressure exceeding a predefined threshold, based on a patient's pHlevel, based on the patient's physical orientation, or based on apredefined time period, among other triggers.

Using various data sensors, including, but not limited to impedance,electrical activity, piezoelectric, pH, accelerometer, inclinometer,ultrasound-based sensors, RF-based sensors, or strain gauge, thestimulator device can determine whether a patient is eating, how muchthe patient is eating, how long the patient is eating, and/or what thepatient is eating, and, based on that information, adjust stimulationparameters accordingly. In particular, pH data may be used to determinewhat kind of food a patient is eating, where the type of food is definedin terms of its acidity.

In one embodiment, the stimulator device senses LES pressure andinitiates stimulation of the LES when the pressure is below apre-defined threshold level for a predefined period of time andterminates stimulation of the LES when the pressure is above apre-defined threshold level for a predefined period of time. LESpressure may be determined by sensing and processing impedancemeasurements, electrical activity measurements, strain gauge, and/orpiezoelectric measurements. One or more of the various measurements areconstantly measured to create a contiguous LES pressure profile. Basedupon the LES pressure profile, the stimulator can modify stimulationparameters, including pulse amplitude, pulse width, duty cycle, pulsefrequency, stimulation initiation time, ramp rate, or stimulationtermination time, to achieve, with respect to the LES pressure, anabsolute amount of change, a percentage amount of change, increases ordecreases above or below a threshold value, increases or decreases basedon time, increases or decreases based on a LES pressure slope, amongother measures of change.

In another embodiment, the stimulator device uses various data sensorsto determine the pulmonary, intra-thoracic, or intra-abdominal pressureand, based on pulmonary, intra-thoracic, or intra-abdominal pressure,create a patient-specific dose, such as a specific pulse amplitude,pulse width, duty cycle, pulse frequency, stimulation initiation time,ramp rate, or stimulation termination time, required to affect LES tone,pressure, or function to the levels needed by that patient.

In another embodiment, the stimulator device uses various data sensorsto determine the esophageal temperature and, based on that temperaturereading, create a patient-specific dose, such as a specific pulseamplitude, pulse width, duty cycle, pulse frequency, stimulationinitiation time, ramp rate, or stimulation termination time.

In another embodiment, the stimulator device uses various data sensorsto determine the esophageal pH and, based on that pH reading, create apatient-specific dose, such as a specific pulse amplitude, pulse width,duty cycle, pulse frequency, stimulation initiation time, ramp rate, orstimulation termination time.

In another embodiment, the stimulator device uses a combination of datainputs from the above described sensors to generate a total score fromwhich a stimulation therapeutic regimen is derived. For example, if thepatient has not eaten for a long time and lays down, a lower (or no)therapy dose would be delivered. Since diurnal GERD is an episodicdisease and certain periods are more vulnerable to a reflux event thanothers, detecting various patient parameters by various means and usingthem in an algorithm enables clinicians to target those specific refluxevents. In addition, in various embodiments, multiple algorithms areprogrammed into the stimulator device so that treatment can be tailoredto various types of diurnal GERD, based upon input relayed by thesensors. In one embodiment, data from any combination of one or more ofthe following parameters is used by an algorithm to determinestimulation protocol: patient feed state including type of intake (viapatient input or eating detection by a physical sensor that can detectand/or evaluate liquids/solids/caloric value); patient position (viainclinometer/accelerometer); patient activity (viaaccelerometer/actimeter); patient reflux profile (via patient input/pHrecording); LES pressure; LES electrical activity; LES mechanicalactivity (via accelerometer in the LES, pressure sensor, impedancemeasure or change thereof); gastric pressure; gastric electricalactivity; gastric chemical activity; gastric temperature; gastricmechanical activity (via an accelerometer in the stomach, pressuresensor, impedance measurement and changes); patient intuition; vagalneural activity; and, splanchnic neural activity. Based on input fromone or more of the above parameters, the algorithm quantifies thevulnerability for a reflux event and modifies accordingly the amplitude,frequency, pulse-width, duty cycle, ramp rate, and timing of stimulationtreatment. The table below lists the parameters, measurements, andvalues used in an exemplary treatment protocol of one embodiment of thepresent invention.

TABLE 3 Parameter Measurement Value LES Pressure Normal 0 Low 1Inclination Upright 0 Supine 1 Feed State Fasting/Pre-prandial 0Post-prandial 1 Time of the day Day time 1 Night time 0 Fat content ofmeal Low 0 High 1 Patient pH Profile Low-risk period 0 High-risk period1 Patient Symptom Input Low-risk period 0 High-risk period 1 GastricActivity Food Absent 0 Food Present 1 Upright Activity Level Low 0 High1 Supine Activity Level High 1 Low 0 Patient Intuition Low Likelihood 0High Likelihood 1

In the table above, each individual parameter is given a score of 1 or 0depending on the value measured. In one embodiment, a summary score istabulated using one or more parameters in the above exemplary algorithmscoring system to determine patient vulnerability to a reflux event.Based on the score, the treatment parameter is modified. Patients with ahigher summary score are indicated for a greater level of treatment. Forexample, a patient with normal LES pressure in the upright position anda pre-prandial state will be at minimal risk for a reflux event and notherapy will be indicated. Conversely, a patient with low LES pressurein the upright position and an immediate post-prandial state will be atthe highest risk for a reflux event and would receive the highest levelof diurnal GERD therapy.

In one embodiment, a measured parameter is used as a modifier foranother parameter. For example, gastric activity showing food absentdoes not have an individual score but modifies the feed state score froma post-prandial score to a fasting/pre-prandial score. In anotherembodiment, a measured parameter has an absolute value that is notimpacted by other measured parameters. For example, patient intuition ofa high likelihood of a reflux event is an absolute parameter thatdelivers the highest level of diurnal GERD therapy irrespective of othersensed parameters.

In one embodiment, the scoring system for certain individual parametersis a scale rather than a binary score. For example, in one embodiment,the score given to LES pressure is within a range from 0-5 based onduration of low pressure. With each incremental 5 minute duration of lowLES pressure, the score increases by one increment.

In another embodiment, different weight is given to differentparameters. For example, in one embodiment, low LES pressure is given anabsolute score higher than post-prandial feed state.

In another embodiment, the scoring system is tailored to be patientspecific. In one embodiment, for example, for a patient with low symptompredictability as ascertained by symptom association with a standard pHtest, patient symptom input is given a lower weight. In anotherembodiment, for a patient with mostly upright reflux on pH testing, theupright position is given a greater weight than the supine position. Inyet another embodiment, for a patient with exercise induced reflux, agreater weight is given to upright activity while the same parameterreceives a low weight or is eliminated from the algorithm in a patientwithout exercise induced reflux.

Accelerometer/Inclinometer Based Stimulation System

In one embodiment, the implantable device includes an accelerometer orinclinometer and a pre-programmed supine stimulation mode intended toautomatically provide the patient with additional stimulation sessionsduring extended time periods in which the patient is in the supineposition, as noted by said accelerometer/inclinometer. When the mode isenabled by a programmer, a supine position detection triggers additionalstimulation sessions based on pre-set programmable conditions. In oneembodiment, additional stimulation sessions will be initiatedautomatically when the following two conditions are met: 1) the patientis supine (based on a programmable range of inclination) for a minimumamount of time (based on pre-set time ranges) and 2) no stimulation wasapplied recently (maximal time programmable). In another embodimentspecific for diurnal GERD patients, the implantable device inhibits ordoes not schedule stimulation where the accelerometer or inclinometerdetects a supine phase or position.

In one embodiment, the supine stimulation mode can be enabled ordisabled by the user via a programmer interface. The supine stimulationmode is available when the implantable device is in “cyclic” and “dose”modes, but not available (grayed out) when the device is in “continuous”and “off” modes. In another embodiment, the supine stimulation mode canbe implemented in conjunction with other stimulation modes, as describedabove, be the only mode of stimulation, or be disabled. In addition,when active, the supine stimulation mode may or may not overrideregularly scheduled stimulations or manually applied stimulations,depending on the programming. Further, when active, the supinestimulation mode may or may not deliver the same stimulation therapyprofile as programmed in the “cyclic”, “dose”, or other modes, asapplicable, depending on the programming.

In one embodiment, when the supine stimulation mode is enabled, anadditional set of specific programmable parameters becomes active on theprogrammer interface. This set includes the following parameters: supinetime; supine time percentage; supine refractory time; supine level;supine retrigger time and, supine cancel.

Supine time defines the period of time that is required for the patientto be in a supine position in order for the first condition listed aboveto be met. Supine time is programmable to a certain time period by theuser. In one embodiment, supine time is set to 1 minute. In anotherembodiment, supine time is set to 5 minutes. In another embodiment,supine time is set to 30 minutes. In yet another embodiment, supine timeis set to 60 minutes, or smaller increments thereof.

Supine time percentage defines the minimum percentage of data pointsrequired during the supine time in order for the first condition listedabove to be met. Supine time percentage is programmable to a certainpercentage by the user. In one embodiment, supine time percentage is setto 50 percent. In another embodiment, supine time percentage is set to70 percent. In another embodiment, supine time percentage is set to 90percent, or smaller increments thereof.

Supine refractory time defines the minimal amount of time required tohave passed from the end of the last stimulation session (scheduled,manual, or supine stimulation) before a new stimulation session may beinitiated via the supine stimulation mode. Supine refractory time isprogrammable to a certain time period by the user. In one embodiment,supine refractory time is set to 30 minutes. In another embodiment,supine refractory time is set to 60 minutes. In another embodiment,supine refractory time is set to 120 minutes. In yet another embodiment,supine refractory time is set to 180 minutes. FIG. 9 is an illustrationof a timeline 900 depicting a stimulation session 905 followed by asupine refractory time period 910. The supine refractory time period 910begins immediately after the end of the stimulation session 905 andcontinues through its pre-programmed duration. No additional stimulationinitiated by the supine stimulation mode can begin until the supinerefractory time period 910 has ended.

Supine level defines the level of inclination required to achieve asupine posture. Supine level is programmable to a range of degrees bythe user. In one embodiment, where the supine level is measured relativeto a horizontal body, supine level is set between 170 and 200 degrees.In another embodiment, supine level is set between 160 and 200 degrees.In another embodiment, supine level is set between 150 and 200 degrees.In yet another embodiment, supine level is set between 140 and 200degrees. In another embodiment, where the supine level is measuredrelative to a vertical baseline, supine level is set to an angle of 50,60, 70, or 80 degrees, where 0 degrees is a vertical position and 90degrees is a horizontal position.

Supine cancel defines the maximum amount of time that can elapse betweenthe end of a stimulation therapy session triggered by supine stimulationmode and the start of a regularly scheduled stimulation therapy sessionthat will cancel the regularly scheduled stimulation therapy session.Supine cancel is programmable to a certain time period by the user. Inone embodiment, supine cancel is set to 30 minutes. In anotherembodiment, supine cancel is set to 60 minutes. In another embodiment,supine cancel is set to 120 minutes. In yet another embodiment, supinecancel is set to 240 minutes. FIG. 10 is an illustration of a timeline1000 depicting a stimulation session 1005 triggered by supinestimulation mode followed by a supine cancel period 1010. The supinecancel period 1010 begins immediately after the end of the supinestimulation mode stimulation session 1005 and continues through itspre-programmed duration. Any regularly scheduled stimulation sessionscheduled during the supine cancel period 1010 will not be initiated.

Supine retrigger defines the maximum amount of time that may elapsebetween the end of a stimulation therapy session triggered by supinestimulation mode and the initiation of another stimulation. In oneembodiment, the supine retrigger period is programmable and may have avalue of 2 4, 6, or 8 hours, or any increment therein. In anotherembodiment, after a predefined threshold, such as 75%, of a supineretrigger period has passed, the stimulator initiates a post-sleepingstimulation, in anticipation of a breakfast meal event, if a verticalposition is sensed. In another embodiment, the stimulator does notinitiate a post-sleeping stimulation if a vertical position is sensed ifless than a predefined threshold, such as 75%, of a supine retriggerperiod has passed. It should be appreciated that an automatically setpost-sleeping stimulation is optional and that stimulation may simply bepreset for a particular time of the day.

In another embodiment, the supine stimulation mode is enteredautomatically based upon the supine time, or time spent in the supineposition. In such cases, where the implantable device was previously ina dose mode, the device will switch to a cyclic mode. The dose modeprovides a pre-programmed stimulation session per time of day while thecyclic mode provides a stimulation session regularly spaced over a givenperiod of time. When entering the supine stimulation mode, the dose modeis cancelled and a cyclic mode is initiated. In one embodiment, anyexisting dose session will be completed and thereafter a block time willbe applied. The block time refers to a programmable period of time inwhich no other stimulation can be initiated, and, in variousembodiments, can be from 1 minute to 4 hours in length. If the dosesession has previously completed before entering the supine stimulationmode, any remaining block time associated with that most previous dosesession is applied. In one embodiment, while in the supine stimulationmode, any programmed dose sessions are ignored by the implantabledevice.

In one embodiment, supine stimulation mode is exited when the oppositecondition necessary for supine stimulation mode entrance is met. Forexample, based on accelerometer readings, when the patient has not beenin the supine position for a predetermined period of time, theimplantable device will exit the supine stimulation mode. At this point,in one embodiment, the device will cancel the cyclic mode and initiate adose mode. Any existing cyclic session will be completed and thereaftera block time will be applied. If the cyclic session has previouslycompleted before exiting the supine stimulation mode, any remainingblock time associated to that most previous cyclic session is applied.Any programmed doses scheduled to occur before the expiration of theblock time are cancelled. Once the block time has expired, thestimulations will continue as per the programmed dose session.

Modifications to Prevent Habituation or Fatigue

Stimulation parameters may also be periodically modified, in accordancewith a predefined schedule or dynamically by real-time physician orpatient control, to reduce, avoid, or prevent the occurrence of musclefatigue, habituation, and/or tolerance. Manipulation of the length ofthe “on” and “off” cycles can be performed while still obtaining thedesired level of LES function. In one embodiment, the length ofstimulation time to achieve the therapeutic goal can be decreased whilethe stimulation off time required for LES function to return to baselinecan be increased. Less time spent in the “on” cycle will result in fewerincidents of muscle fatigue.

In another embodiment, the “on” and “off” cycles, as describedpreviously, can cycle rapidly. For example, during a 30 minute period,the stimulation may be on for 3 seconds and off for 2 seconds during theentire 30 minute period. In another embodiment, a stimulation regime hasan “on” period of 0.1 seconds to 60 seconds and an “off” period of 0.1seconds to 60 seconds that cycle over 24 hours.

In another embodiment, the patient can take a “stimulation holiday”. Inother words, stimulation can be further stopped for a time periodgreater than the “off” cycle to allow the muscle to recover. Greatlyincreasing the time period in which there is no stimulation also servesto avoid muscle fatigue and tolerance.

In another embodiment, stimulation parameters can be intermixed in anattempt to avoid muscle fatigue, habituation, and/or tolerance whilestill obtaining the desired level of LES function. For example,alternating short pulses can be intermixed with intermediate pulses tostimulate the LES. The variation in stimuli received by the muscle willassist in avoiding fatigue and tolerance.

In another embodiment, stimulation electrode can be changed in anattempt to avoid muscle fatigue, habituation, and/or tolerance whilestill obtaining the desired level of LES function. For example, oneelectrode can function as the anode for certain duration and thenfunction as a cathode for another duration allowing for different partsof the LES muscle to be stimulated. The variation can occur in a singlestimulation session, from session to session, from day to day, week toweek or month to month or any duration thereof. The variation in theparts of the LES muscle to be stimulated will assist in avoiding fatigueand tolerance.

In another embodiment, LES function can be improved or normalized usingthe present invention without raising LES pressure above the mid-normalrange. This is achieved by minimizing the energy delivered to the muscleto, but not beyond, the point where the LES regains improved function.Less energy delivered results in less fatigue and tolerance.

In another embodiment, LES function can be improved or normalized usingthe present invention without raising LES pressure above the low-normalrange. This is achieved by minimizing the energy delivered to the muscleto, but not beyond, the point where the LES regains improved function.Less energy delivered results in less fatigue and tolerance.

In another embodiment, LES function can be improved or normalized usingthe present invention without raising LES pressure but by altering otherLES functions such as LES compliance. This is achieved by minimizing theenergy delivered to the muscle to, but not beyond, the point where theLES regains improved function. Less energy delivered results in lessfatigue and tolerance.

In another embodiment, the stimulation parameters can be changed, suchas by modifying pulse width, frequency, amplitude, ramp rate, the dutycycle, or the choice of stimulating electrode on a predefined periodicbasis to avoid having the muscles habituate to a known and repeatedstimulation setting. In such an embodiment, a stimulator may locallystore a plurality of different stimulation parameters which areimplemented in accordance with a predefined schedule. The stimulator mayalso store a single set of stimulation parameters, each parameter havingan acceptable range of operation, and then randomly implement astimulation parameter bounded by the acceptable ranges of operation.

Electrode Configurations and Methods of Placing and Confirming thePlacement of Electrodes

In one embodiment, the therapeutic objectives described herein areachieved by at least one of a plurality of different electrodeconfigurations, as shown in FIG. 11. It should be appreciated that, inone embodiment, the electrode placement, as shown, at least partlyenables the patient's LES function to improve or normalize,post-stimulation, and/or the patient's LES pressure to increasepost-stimulation. The electrode configurations described herein may beused in accordance with any of the stimulation parameters, systemarchitectures, and sensing systems described herein.

Within the esophagus 1100, and more particularly the LES, a plurality ofdifferent electrode combinations can be used to achieve the therapeuticand operational objectives described herein. In one embodiment, a firstelectrode 1105 is placed proximate to the left lateral wall of theesophagus 1100 and operated in combination with a second electrodeplaced proximate to the right lateral wall 1110 of the esophagus 1100.In one embodiment, a first electrode 1105 is placed proximate to theleft lateral wall of the esophagus 1100 and operated in combination witha second electrode placed in the anterior proximal wall 1115 of theesophagus 1100. In one embodiment, a first electrode 1110 is placedproximate to the right lateral wall of the esophagus 1100 and operatedin combination with a second electrode placed in the anterior proximalwall 1115 of the esophagus 1100. In another embodiment, a firstelectrode 1105 is placed proximate to the left lateral wall of theesophagus 1100 and operated in combination with a second electrodeplaced in the anterior, distal wall 1120 of the esophagus 1100. In oneembodiment, a first electrode 1110 is placed proximate to the rightlateral wall of the esophagus 1100 and operated in combination with asecond electrode placed in the anterior, distal wall 1120 of theesophagus 1100. In another embodiment, a first electrode 1115 and asecond electrode 1120 are placed proximally and distally in the anteriorwall of the esophagus 1100. In another embodiment, more than one of theabove described combinations are used serially along the length of theesophagus 1100.

Referring to FIG. 12, the electrodes 1205, 1210, 1215, 1220 can beplaced longitudinally or transversely or in any orientation relative tothe length of the esophagus 1200 and can be implemented in the sameexemplary combinations described in relation to FIG. 11. It should beappreciated that not all of the electrodes shown in FIG. 11 need to beimplanted or operated concurrently. For example, to achieve any of theaforementioned therapeutic objectives, only one pair of electrodes, suchas 1105 and 1110 or 1115 and 1120 need be implanted and/or operatedconcurrently.

In another embodiment, shown in FIG. 13, electrodes can be implanted inseries with two electrodes 1310, 1305 proximate to the left lateral wallof the esophagus 1300 and two electrodes 1315, 1320 proximate to theright lateral wall of the esophagus 1300. These electrodes can beactivated in various combinations, as described above, to provide forthe optimal normalization of LES pressure, with minimal energy deliveredto the tissue and minimal muscle fatigue or depletion ofneurotransmitter storages. It should be appreciated that stimulationparameters (amplitude, timing of stimulation session and switching ofelectrode configuration) will be set so as to activate release ofappropriate neurotransmitter. Such parameters can vary between patientsdue to surgical variation and physiological sensitivity. The electrodeactivation or implantation combinations can include electrodes 1310 and1315, electrodes 1310 and 1305, electrodes 1315 or 1320, electrodes1310/1315 alternating with 1305/1320, and electrodes 1310/1305alternating with 1315/1320.

It should be appreciated that the length and surface area of theelectrode and the distance between the electrodes can affect the degreeand duration of the patient's post-stimulation normalization of LESfunction. It should further be appreciated that the length and surfacearea of the electrode can affect the current amplitude required toincrease LES pressure post-stimulation.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting the electrodes in a“linear” configuration. This is accomplished by implanting a firstelectrode axially along the length of the smooth muscle of the LES,shown as 1115 in FIG. 11, and implanting a second electrode 1120 belowand substantially in alignment with the first electrode 1115. The bottomof the first electrode 1115 is separated from the top of the secondelectrode 1120 by a distance of no greater than 5 cm, preferably nogreater than 2 cm, and most preferably approximately 1 cm. Eachelectrode is placed preferably more than 1 mm away from the vagal trunk.This electrode configuration is supplied a stimulation pulse from astimulator. The stimulation pulse may be delivered in accordance withany of the aforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec and a pulse repetitionfrequency of 20 Hz. A stimulator may further be configured to detect anyof the aforementioned biological parameters, including LES pressure. Inone embodiment, the LES pressure is derived from a sensor adapted togenerate an impedance measurement. In one embodiment, LES pressure isderived from piezoelectric sensors or electrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting the electrodes in a“parallel” configuration. This is accomplished by implanting a firstelectrode axially along the length of the smooth muscle of the LES,shown as 1105 in FIG. 11, and implanting a second electrode 1110 axiallyon the other side of the esophagus 1100, parallel to the first electrode1105. The distance between the first electrode 1105 and the secondelectrode 1110 is less than half the circumference of the LES. Theelectrodes 1105, 1110 are implanted in the anterior of the LES, withpreferably at least one electrode being in the right anterior (thisplaces the stimulation as far as possible from the heart). Eachelectrode is placed preferably more than 1 mm away from the vagal trunk.This electrode configuration is supplied a stimulation pulse from astimulator. The stimulation pulse may be delivered in accordance withany of the aforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec. A stimulator mayfurther be configured to detect any of the aforementioned biologicalparameters, including LES pressure. In one embodiment, the LES pressureis derived from a sensor adapted to generate an impedance measurement.In one embodiment, LES pressure is derived from piezoelectric sensors orelectrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodetransaxially across the length of the smooth muscle of the LES, shown as1215 in FIG. 12, and implanting a second electrode 1220 substantiallyparallel to the first electrode and spaced apart from the firstelectrode 1215 a distance of no greater than 5 cm. This electrodeconfiguration is supplied a stimulation pulse from a stimulator. Thestimulation pulse may be delivered in accordance with any of theaforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec. A stimulator mayfurther be configured to detect any of the aforementioned biologicalparameters, including LES pressure. In one embodiment, the LES pressureis derived from a sensor adapted to generate an impedance measurement.In one embodiment, LES pressure is derived from piezoelectric sensors orelectrical activity based sensors.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodeand a second electrode in a configuration that concentrates currentdensity at two or fewer points close to each electrode. This electrodeconfiguration is supplied a stimulation pulse from a stimulator. Thestimulation pulse may be delivered in accordance with any of theaforementioned stimulation parameters. In one embodiment, thestimulation pulse has a pulse amplitude no greater than 15 mAmp and morepreferably no greater than 8 mAmp. In one embodiment, the stimulationpulse has a pulse width of approximately 200 μsec.

In one embodiment, a patient is treated to achieve any one of theaforementioned therapeutic objectives by implanting a first electrodeand a second electrode in a configuration that avoids distributingsubstantially all of the current density along the lengths of eachelectrode. This electrode configuration is supplied a stimulation pulsefrom a stimulator. The stimulation pulse may be delivered in accordancewith any of the aforementioned stimulation parameters. In oneembodiment, the stimulation pulse has a pulse amplitude no greater than15 mAmp and more preferably no greater than 8 mAmp. In one embodiment,the stimulation pulse has a pulse width of approximately 200 μsec.

Variations in the stimulation and placement of electrodes also conveythe added benefit of avoiding muscle fatigue and tolerance, aspreviously discussed. For example, as shown in FIG. 12, two pairs ofelectrodes, 1205/1210 and 1215/1220, can be implanted and stimulated inalternative succession. In one embodiment, the two pairs of electrodesreceive simultaneous stimulations with the same stimulation parameters.In another embodiment, the two pairs of electrodes receive sequentialstimulations with the same stimulation parameters. In anotherembodiment, the two pairs of electrodes receive simultaneousstimulations with different stimulation parameters. In anotherembodiment, the two pairs of electrodes receive sequential stimulationswith different stimulation patterns. Electrode placement can also bemanipulated to decrease muscle fatigue and tolerance. In one embodiment,the two pairs of electrodes are placed so that the distance between anyset of electrodes is less than 2× the distance between the pair ofelectrodes, resulting in the stimulation from a set of electrodesstimulating less than 100% of the LES.

Preferably, during the implantation process, electrode configurationsare tested to verify that the proper configuration has been achieved. Inone embodiment, a catheter or endoscope configured to measure LESpressure in combination with a manometer is proximate to theimplantation area while the newly implanted electrodes are stimulated.LES pressure is measured before, during, and/or after stimulation. Ifthe desired LES pressure profile is achieved, the implantation is deemedsuccessful and the testing may terminate. If the desired LES pressureprofile is not achieved, the electrode configuration may be modified.LES pressure testing is then repeated until the proper LES pressureprofile is achieved. Other sensed data, such as temperature, may also beused in this testing process. It should be appreciated that the testingprocess can be conducted separate from the implantation procedure. Forexample, patients can be tested with temporary electrodes, insertednon-invasively (nasogastric, for example), and upon success can bedeemed suitable for implant.

In another embodiment, the stimulating electrodes can be switchedpost-implantation to deliver the electrical stimulation to the chosenelectrode that is more ideally placed to achieve the desired clinicaloutcome. This allows adapting and accommodating to changes due toelectrode—tissue interaction over time which may affect the desiredclinical outcome.

Stimulator Energy Storage and Sensing Systems Non-Sensing ActiveImplantable Medical Devices

The embodiments disclosed herein achieve one or more of the above listedtherapeutic objectives using stimulation systems that are energyefficient and do not require sensing systems to identify wet swallows,bolus propagation, or patient symptom changes, thereby enabling a lesscomplex, smaller stimulation device which can more readily be implantedusing endoscopic, laparoscopic or stereotactic techniques. The disclosedstimulation methods permit a natural wet or bolus swallow to overridethe electrically induced stimulation effect, thereby allowing for anatural wet or bolus swallow without having to change, terminate, ormodify the stimulation parameters.

It should be appreciated that, in one embodiment, the stimulation devicereceives energy from a remote energy source that is wirelesslytransmitting ultrasound or RF based energy to the stimulation device,which comprises receivers capable of receiving the energy and directingthe energy toward stimulating one or more electrodes. It should furtherbe appreciated that the device may be voltage driven or current driven,depending upon the chosen embodiment.

It should be appreciated that, in another embodiment, the stimulationdevice is a macrostimulator that receives energy from a local energysource, such as a battery, and directs the energy toward stimulating oneor more electrodes. It should further be appreciated that the device maybe voltage driven or current driven, depending upon the chosenembodiment.

By not requiring sensing systems that identify wet swallows, boluspropagation, or patient symptom changes, at least certain embodimentscan operate with increased reliability and also be smaller in size. Thesmaller device size results in increased patient comfort, allows forplacement (implantation) in the patient in more appropriate and/orconvenient locations in the patient's anatomy, and allows the use ofdifferent surgical techniques for implantation (laparoscopic,endoscopic) and/or smaller incisions, which are less invasive, causeless trauma, cause less tissue damage, and have less risk of infection.The small size can also allow placement of a larger number of devices soas to provide redundancy, improved clinical efficacy, durability andreliability.

In addition to the absence of certain components which, conventionally,were required to be part of such an electrical stimulation system,embodiments of the present invention can achieve the above-listedtherapeutic objectives using stimulation systems that operate at lowenergy level, such as at or below 20 Hz with a current of at or below 8mAmp, preferably 3 mAmp, and a pulse width of 200 μsec.

As a result of the operative energy range, the following benefits can beachieved: a) a wider range of electrode designs, styles, or materialsmay be implemented, b) the need to use special protective coatings onelectrodes, such as iridium oxide, or titanium nitride, while stillmaintaining electrode surface areas below 5 mm², is eliminated, c) onehas the option of using small electrode surface areas, preferably belowa predefined size with coatings to increase the effective surface area,such as iridium oxide, or titanium nitride, d) one can operate inwireless energy ranges that are within regulatory guidelines and safetylimits and do not pose interference issues, such as a RF field strengthbelow a predefined limit and ultrasound field strength below apredefined limit.

It should further be appreciated that the presently disclosed systemscan be implemented using a variety of surgical techniques, includinglaparoscopic and endoscopic techniques. In one embodiment, alaparoscopically implanted device comprises a battery providing localenergy storage and only optionally receives energy through wirelesstransfer, such as RF or ultrasound. In such an embodiment, the devicestimulates at a higher amperage for shorter periods of time, relative toembodiments without local energy storage, thereby allowing for longeroff cycles, lower duty cycles, and better battery efficiency. In oneembodiment, an endoscopically implanted device may or may not comprise alocal energy storage device but does comprise a wireless receiver toreceive energy wirelessly transmitted from an external energy source andtransmission device. In such an embodiment, this device stimulates at alower energy setting for longer on cycles and shorter off cycles,relative to the embodiment with local energy storage, thereby having agreater duty cycle than a laparoscopic implant.

The stimulators of the present invention, when properly programmed inaccordance with the stimulation parameters described herein andassociated with the appropriate electrode configurations, exhibit a highdegree of energy efficiency. In one embodiment, the electricalstimulation device initiates electrical stimulation based upon aninternal clock or a patient activated trigger. Electrical stimulationthen continues for a pre-set or predefined period of time. Referencing a24 hour period of time, the preset or predefined period of time may beequal to an “on” time period that is less than or equal to 24 hours, 12hours, 1 second, or any increment therein. Upon completion of thatpredefined period of time, the internal clock then causes the electricalstimulation device to terminate electrical stimulation.

It should be appreciated that any activation by an internal clock can beconfigured to cycle daily or a few times daily or be synchronized tomeal times, as signaled manually by a patient. It should further beappreciated that the timing of meal times or other physiologicallyrelevant events can be saved and/or learned, thereby enabling the deviceto default to standard initiation of stimulation time or termination ofstimulation time based upon past data gathered. The setting ofstimulation times may be set by a physician, based on an interview witha patient or based on the detection of eating using pH sensing or someother automated eating detection mechanism. In one embodiment,stimulation is initiated in advance of a predefined meal time to achievean increase in LES tone before the patient eats. For example, if apatient's predefined meal time is 2 pm, then stimulation is set toinitiate in advance of 2 pm, such as 1:30 pm. If the patient thenreports symptoms between 4-6 pm, then, in the future, stimulation may bereinitiated at 3 pm. If a patient's predefined meal time is 12 pm, thenset stimulation is set to initiate in advance of 12 pm, such as 11:30am. If the patient then reports symptoms between 2-4 pm, stimulation maybe reinitiated at 1 pm.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. Upon completion of that predefined periodof time, the internal clock then causes the electrical stimulationdevice to terminate electrical stimulation. This ratio of the predefinedperiod of stimulation relative to the time where electrical stimulationis terminated is less than 100%, up to a maximum duty cycle, such as70%, 75%, 80%, 85%, 90%, 95%, or any increment therein.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is up to a maximum “on” period, suchas 12 hours, during which the device may be continually operating. Uponcompletion of that predefined period of time, the internal clock thencauses the electrical stimulation device to terminate electricalstimulation.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is up to a maximum “off” period, suchas 12 hours, during which the device is not operating. Upon completionof that predefined period of time, the internal clock then causes theelectrical stimulation device to restart electrical stimulation.

In another embodiment, the electrical stimulation device initiateselectrical stimulation based upon an internal clock or a patientactivated trigger. Electrical stimulation then continues for a pre-setor predefined period of time. The pre-set or predefined period of timemay be equal to a time period that is less than the time required to seea visible or measurable change in the LES pressure or function. Uponcompletion of that predefined period of time, the internal clock thencauses the electrical stimulation device to terminate electricalstimulation. The desired increase in LES pressure or improvement in LESfunction occurs or persists post-stimulation, followed by a decrease inLES pressure or function which still remains above a pre-stimulationstate after a period of >20 minutes.

It should be appreciated that other stimulation protocols, which resultin the desired effect of operating for less than 100% of duty cycle andwhich have a pre-set or predefined period of non-stimulation, can beachieved using combinations of turning on and off subsets of electrodesat different times. For example, one may turn a first subset ofelectrodes on, turn a second subset of electrodes on, then turn allelectrodes off, followed by turning a second subset of electrodes on,turning a first subset of electrodes on, and then all electrodes offagain.

Sensing Active Implantable Medical Devices

It should be appreciated that the present invention can be optionallyoperated in combination with sensing systems capable of sensingphysiological events, such as eating, swallowing, a bolus propagatingthrough the esophagus, muscle fatigue, pH level, esophageal pressure,tissue impedance, LES tone/pressure, patient position, sleep state, orawake state. In such a case, a physiological event can be used to modifythe stimulation schedule by, for example, extending the stimulation timeperiod based upon sensed pH level, eating, swallowing, or a boluspropagating through the esophagus or, for example, terminating thestimulation period before the preset time period expires based uponsensed muscle fatigue.

It should also be appreciated that the present invention can be drivenby, and fully triggered by, sensing systems capable of sensingphysiological events, such as eating, swallowing, a bolus propagatingthrough the esophagus, muscle fatigue, pH level, esophageal pressure,tissue impedance, LES tone/pressure, patient position, activity level,sleep state, or awake state. In such a case, a physiological event canbe used to initiate the stimulation schedule.

By operating the stimulation system less than 100% duty cycle and havingthe stimulation device be off during preselected periods, the presentlydisclosed stimulation system uses less energy than prior art devices.Accordingly, the stimulation systems disclosed herein can effectivelyoperate to achieve the above-listed therapeutic objectives using anenergy source local to the stimulator that a) does not include abattery, b) includes a small battery capable of being recharged from anexternal energy source, c) only includes a capacitor and, morespecifically, a capacitor having a rating of less than 0.1 Farads or d)only includes a battery that is not rechargeable.

In one embodiment, a stimulator uses a remote data sensor forautomatically adjusting parameters. The stimulator comprises stimulatingcircuitry contained within a housing that includes a power source, meansfor delivering stimulation, a receiver to collect data from a remotesensor and a control unit that analyzes the data received from thereceiver and adjusts the stimulation parameters based on a plurality ofstored programmatic instructions and the received data. The means forstimulation may include any form of leaded or a leadless device. Thestimulator element would preferably be implanted either under the skin,in cases where the stimulator comprises a macrostimulator internal pulsegenerator (IPG), or close to the stimulation area, in cases where thestimulator comprises a microstimulator. The stimulator can also comprisea plurality of separate units, in separate housings, including, forexample, an external control unit and receiver and an implantablestimulator, similar to a passive microstimulator.

The stimulator is in wireless or wired data communication with one ormore sensor elements. The sensor elements are implanted in an area thatallows the sensor to collect physiological data relevant to thecontrolling the operation of the stimulator. Each sensor elementincludes means for sensing the required physiological function and meansfor transmitting the data to the control unit. In one embodiment, thesensor element comprises a capsule adapted to measure physiological pHand transmit pH data from within the lumen of the esophagus to animplantable stimulator device. In another embodiment, the sensor elementcomprises a pH sensor located within a nasogastric tube and means fortransmitting the pH data to an implanted control unit. In anotherembodiment, the stimulator comprises electrodes implanted in the LESthat are wired to an implantable IPG, which is in data communicationwith a pH measuring element, such as but not limited to a pH capsule ora catheter based device, that is transmitting pH data to the device viauni-directional or bi-directional communication.

In another embodiment, the stimulator/sensing system disclosed hereincan locally store a plurality of programmatic instructions that, whenexecuted by circuitry within the IPG, uses data received from a capsuleto automatically refine stimulation parameters within a pre-definedrange of boundaries. The data may be continuously streamed from thesensing capsule to the IPG and may be subject to continuous monitoringand processing. The data may comprise any one of pH data, pressure data,LES pressure data, temperature, impedance, incline, or otherphysiological data.

Referring to FIG. 14, a patient 1400 has implanted within his tissue astimulator 1415, as further described below. The stimulator 1415 isadapted to dynamically communicate with a temporary sensor 1410, asfurther described below, which may be located inside the patient's GIlumen. The implanted stimulator 1415 comprises stimulator circuitry andmemory having programmatic instructions that, when executed, perform thefollowing functions: transmit an interrogating signal designed to elicitor cause a transmission of sensed data from the temporary sensor 1410 orreceive a transmitted signal comprising sensed data from the temporarysensor 1415 and process the sensed data to modify stimulationparameters, such as frequency, duration, amplitude, or timing.Optionally, the stimulator 1415 may also analyze the received senseddata signal to determine if the data is reliable. The implantedstimulator 1415 is adapted to only modify stimulation parameters orotherwise engage in a processing routine adapted to use the sensed datato determine how the simulation parameters should be modified when itsenses and receives the sensed data. Optionally, the implantedstimulator 1415 is adapted to modify stimulation parameters or otherwiseengage in a processing routine adapted to use the sensed data incombination with patient data inputted into an external device todetermine how the simulation parameters should be modified.

For example, where a meal event, sleeping event, or other event whichmay cause, be related to, or be associated with a diurnal GERD event, isexpected to occur at a specific time during the day (either becausepreviously sensed data has determined a pattern indicating the existenceof such an event or because patient data expressly indicates that suchan event should be expected), stimulation parameters may be modified orotherwise established in order to provide the requisite level, degree oramount of stimulation before the anticipated event, such as 5 minutes,10 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 120 minutes,or some increment therein. The determination of stimulation parameters,including start time, end time, pulse frequency, duration, ramp rate,duty cycle, and/or amplitude, can be determined independent of thepatient's immediate physiological state and not causally related to thepatient's existing condition. Rather, historical data patterns fromsensors, including pressure data, LES pressure data, temperature,impedance, incline, or other physiological data, can be used to definethe diurnal GERD profile of a patient, namely when, in the course of aday, a patient is likely to experience a diurnal GERD event, and thenused to proactively normalize LES function in advance of the diurnalGERD event. To properly generate and mine data patterns, it ispreferable to capture both the magnitude of the physiological data (i.e.pH<4), the duration (for one hour), and the timing (around 1 pm). It isfurther preferable to associate different physiological data with eachother to see if a predictive pattern may exist between data sets and tofurther correlate that data with the patient's own reporting of pain,discomfort, acid reflux, or other sensations to better determine when adiurnal GERD event is likely to occur in a day.

In one embodiment, the implanted stimulator 1415 is configured to checkthe reliability of the data by processing it to determine whether thedata is indicative of the sensor being in an improper location. In oneembodiment where the temporary sensor is a capsule measuring pH dataintended to measure esophageal pH, such a determination process may beconducted by: a) monitoring the received pH data over a predefinedperiod of time to determine if it is indicative of a high pHenvironment, such as the patient's stomach as opposed to the esophagus,b) monitoring the received data signal, such as an RF signal, over apredefined period of time to determine if the signal strength hassignificantly changed or modified, indicating a change in physicallocation, or c) monitoring a received accelerometer or inclinometer datasignal from the pH capsule, over a predefined period of time, todetermine if the capsule is in a proper physical orientation. Dependingon the reliability check, the implanted stimulator 1415 may use, ordiscard, the sensed data. If no reliable data is received by theimplanted stimulator 1415, it does not modify stimulation parameters orotherwise engage in a processing routine adapted to use the sensed datato determine how the simulation parameters should be modified. Ifreliable data is received by the implanted stimulator 1415, it modifiesstimulation parameters or otherwise engages in a processing routineadapted to use the sensed data to determine how the simulationparameters should be modified.

The temporary sensor 1410 may store the sensed and transmitted data andtransmit the stored data to an external reading device. It should beappreciated that the previously discussed methods for using sensed data,whether from a temporary sensor or permanently implanted sensor, may beperformed by an external device. For example, an external device maywirelessly receive sensed data and use the sensed data to determine apattern indicative of when a diurnal GERD event is likely to beexperienced by a patient. Any pattern analysis method known to personsof ordinary skill in the art may be used. The data may include some orall of the sense data, externally inputted patient data, or acombination thereof. As discussed above, the external device would usethe data to determine the time(s) of day when a patient typicallyexperiences a diurnal GERD event and the appropriate stimulationparameters required to normalize LES function prior to such diurnal GERDevent. The requisite stimulation parameters may be determined byexamining historical diurnal GERD events in relation to stimulationparameters that had been implemented and modifying the stimulationparameters to increase or decrease the magnitude or duration of thestimulation accordingly. Additionally or alternatively, the implantedstimulator 1415 may store the sensed data and data indicative of howstimulation parameters, such as frequency, duration, amplitude, ortiming, were modified based on the sensed data, and transmit the storeddata to an external reading device.

Referring to FIG. 15, in one embodiment, the process 1500 implemented bythe stimulator system comprises collecting 1505 pH data periodically orcontinuously over a predefined period, such as 1, 2, 6, 12, 24, 36, 48,or 60 hours, or any time increment in between. Circuitry within thestimulator analyzes the pH data 1510 to determine if, within thepredefined period, such as 24 hours, pH is less than a predefined value,such as 4, for a percentage of time higher than a threshold value, suchas 1, 2, 3, 4, 5, 10, 15, or 20 hours, or any increment therein 1515.The processor may analyze pH data 1510 by integrating periods in whichthe pH is less than the predefined value compared with stimulation timesand separately integrate periods with stimulation in a most recent timeperiod (i.e. last 6 hours) to periods without stimulation in the mostrecent time period.

If the percentage of time with the pH less than the predefined valuewithin a predefined period is lower than a threshold value, such as 1percent or lower 1520, then the circuitry may adjust stimulationparameters 1525 so as to reduce the timing, frequency, or size of thestimulation doses. In one embodiment, the circuitry decreases dailystimulations or amplitudes by a discrete amount, such as 1 mAmp. In oneembodiment, the system may not reduce the timing, frequency, or size ofthe stimulation doses below a minimum dose.

If the percentage of time with the pH less than the predefined valuewithin a predefined period is greater than a threshold value, such as 5percent or higher 1515, then the circuitry may further analyze 1530whether there were more periods with pH being greater than the thresholdvalue during which there was no stimulation than with stimulation. Ifthere were more periods with pH being greater than the threshold valueduring which there was no stimulation than with stimulation, thecircuitry may increase the number of daily stimulations by a discreteamount, such as by 1 1535 or the duty cycle or length of a givenstimulation session or duration by a discrete amount, such as 1 minute.By doing so, the system assumes the amount of energy delivered perstimulation is sufficient, but there simply were not enough stimulationevents in a day, or the stimulation was not long enough. If there weremore periods with pH being greater than the threshold value during whichthere was stimulation than with no stimulation, the circuitry increasesthe amplitudes of stimulations by a discrete amount, such as by 1 mAmp1540. By doing so, the system assumes the amount of energy delivered perstimulation was not sufficient and therefore increases the energydelivered per stimulation. In one embodiment, the system may notincrease the timing, frequency, or size of the stimulation doses above amaximum dose.

In general, if the percentage of time within a predefined period duringwhich pH is less than a threshold value, such as 4, is higher than anupper value, such as 5%, then the stimulation parameters will beadjusted so as to increase dose. Also, if the percentage of time withina predefined period during which pH is less than a threshold value, suchas 4, is lower than a lower value, such as 1%, then the stimulationparameters may be adjusted so as to reduce dose. The decreasing andincreasing of dose will be done based on the temporal behavior of the pHvalues. It should be appreciated that doses may be incremented by anyamount. It should further be appreciated that doses can be effectivelydecreased or increased by increasing one parameter while reducinganother parameter so that the total energy is increased, reduced, orunchanged. Finally, it should be appreciated that all modifiableparameters will be bounded, on at least one of the maximum or minimumboundary, by a range defined by a healthcare provider.

In another embodiment, the operation of the system is augmented withother sensed data. Where the system is being used to stimulate the LESor treat diurnal GERD, pH sensor data can be augmented withaccelerometer and/or inclinometer data. The accelerometer orinclinometer sensor(s) could be located within the implantable device orin another device on or inside the patient body. This additional datacan enable the control unit algorithm to assess patient modes (e.g.,sleep, exercise, etc) and thereby to improve the tuning of stimulationparameters for a specific patient, thereby improving device efficacyand/or efficiency. Additional sources of information may include, butnot be limited to, pressure measurement or an impedance measurement by acapsule or an eating detection mechanism using one or more sources suchas impedance or other electrical or electromechanical measurement fromwithin the tissue or from the lumen. These additional sources ofinformation can further be used by the control unit to adjust thestimulation dose and other parameters and other functions of theimplantable device. It should be appreciated that any of theaforementioned data may be used individually or in combination to modifythe operation of the system and, in particular, to determine howstimulation parameters should be modified to address an anticipatedpatient diurnal GERD event.

In another embodiment, the system logs the sensed and computed data anddownloads the data to an external device for viewing and analyzing by amedical professional or a technician. By permitting on-demand or batchdownloading, the system can eliminate the need for the patient to carryan external receiver during pH-sensing, thereby improving the useexperience of the patient and potentially improving compliance andallowing for longer measurement periods. The system can download dataautomatically and without any requirement for user intervention, such aswhen an appropriately calibrated external device comes within a datacommunication area of the implanted device, or semi-automatically, suchas when initiated by the implantable device when the implantable deviceis in proximity (communication distance) of the external device and theuser has provided a password or other indication of approval via theexternal wireless interrogation device.

It should be appreciated that the external device receiving the sensedor computed data could be located at the healthcare provider's locationor at the patient's home. If captured at the patient's home, the datacould be automatically sent to the clinic for physician review and/orapproval of suggested parameter changes via any communication medium,including Internet, Ethernet network, PSTN telephony, cellular,Bluetooth, 802.11, or other forms of wired or wireless communication.The transmitted data preferably contain the measured values, therecommended stimulation parameters adjustments, or both. Similarly, thephysician approval, or physician suggested parameter changes, could besent back to the external device located at the patient's home which, inturn, transmits appropriate commands to the implanted device, when thetwo devices are in proximity, to initiate the suggested parameterchanges.

In another embodiment, the system monitors sensor, such as capsule,failure. If the sensor fails an internal diagnostic test, a failure oralert signal is transmitted to the implanted control unit, or theimplanted control unit itself logs a failed attempt to communicate with,or obtain uncorrupted data from, the sensor. The control unit thentransmits that failure or alert signal data to the external device and,in turn, to the healthcare provider, as described above, therebyalerting a healthcare provider that the patient needs to return to havethe sensor fixed or another sensor implanted.

In another embodiment, the system is capable of recognizing andregistering a plurality of different sensing devices, such as capsules,and re-initiate newly implanted sensors as required to ensure continuousor substantially continuous measurement. For example, the stimulator canbe implanted for a long period of time, such as several months or years,and for a shorter period of time, such as once per annum, a sensor isimplanted. The stimulator registers the new sensor and automaticallyadjusts the new sensor for operation in the particular anatomicalregion, such as the esophagus.

In addition to failing, sensors may migrate out of the implantedanatomical region. For example, where a sensor, such as a capsule, hasbeen implanted into a patient's esophagus but has migrated to thestomach, the physical location of the sensor can be derived by examiningthe sensed data. For example, where a pH capsule has moved from theesophagus to the stomach, the capsule will likely transmit dataindicative of extensively long periods during which the pH is highlyacidic. In that case, the stimulator system can assume the capsule hasmigrated, report this failure to an external device, and ignore futuredata being transmitted from the capsule or record the data but not relyupon it for parameter setting. Similarly, the stimulation system mayregister a weaker or changed signal, indicative of a sensor moving adistance away from the recording device.

The presently disclosed stimulator system may further comprise areceiving antenna integrated into a stimulator system, which may be usedfor energy transfer to the stimulator system and communication to andfrom the device. The close proximity between the stimulator,particularly a miniature device, and a sensor, such as the pH capsule,can be used to achieve communication efficiency and increase durabilitythrough a miniature antenna in the stimulator that can accept data fromthe pH capsule. The close distance can effectively reduce powerrequirements and enables typical low frequency inductively coupledtelemetry for transmission through titanium via coils; as well as highfrequency RF communication such as MICS or IMS bands via monopole,dipole, or fractal electric field antennas. The communication distancecan be further reduced by enabling anchoring of the pH capsule ornasogastric tube to the implanted control unit. This can be facilitatedby, for example, a magnetic force between the two units caused by amagnet in both units or a magnet in one unit and a ferrous metal in theother.

One of ordinary skill in the art would appreciate that other means forcommunication can be used that will take advantage of the closeproximity between the stimulating electrodes and the sensing device,such as a pH capsule, even when the control unit is farther away,thereby allowing for a significant reduction in the power consumptionand improvement of reliability of communication. The stimulatingelectrodes in that embodiment would serve as receiving antennas and alsosimplify the design of the control unit, thereby avoiding the need for areceiving coil, antenna or other electromagnetic receiving means.

Bi-directional communication between the control unit and the sensorunit can be implemented as part of the system to allow, for example,calibration or activation of specific actions such as additionalmeasurements, determination of measurements to be taken, determinationof measurement times, local stimulation by the sensor unit, among othervariables. The sensor unit can also be used to not only transmit thesensed data, but also to transmit energy for charging and powering thecontrol unit and the stimulating device. For example, pH capsules thatfurther acts as an energy recharging source can be periodicallyimplanted, as required, to deliver energy to the control unit or amicro-stimulator in addition to actually sensing pH data.

Patient Selection Methods

In one embodiment, a person is permitted to practice the treatmentsystems and methods disclosed herein and, in particular, to have anembodiment of the electrical stimulation systems disclosed hereinimplanted into him or her only if the person passes a plurality ofscreening or filtering steps.

In one embodiment, a plurality of physiological measurements are takenof the patient and used to determine whether the patient maytherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein. LES pressure data and/or pH datais collected from the patient. For example, pH measurements are obtainedover a period of time, such as 4, 8, 12, 16, 20, or 24 hours or someincrement therein. The amount of time within the predefined measurementperiod during which the pH measurement is above a predefined thresholdindicative of acid exposure, such as a pH of 4, is calculated. Thenumber of acid exposure events occurring for more than a predefinedperiod of time, such as more than 1, 3, 10, 15, or 20 minutes, or anyincrement therein, is determined. The total time for each acid exposureevent lasting more than the predefined period of time, i.e. 3 minutes,referred to as a long event, is then summed. If that total time exceedsa predefined threshold, such as 5 minutes to 240 minutes or anyincrement therein, it may be concluded that the patient wouldtherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein. For example, if a patient has 4events of acid exposure lasting 1, 4, 5 and 6 minutes and the predefinedthreshold is 3 minutes, the total time would be equal to 15 minutes(4+5+6). If the total time threshold is 10 minutes, then the patient canbe categorized as an individual who would benefit from the electricalstimulation treatment systems and methods disclosed herein.

Another physiological measurement that may be used to select eligiblepatients is LES end expiratory pressure (LES-EEP). In one embodiment, apatient's LES-EEP is measured and collected during resting time, e.g. noswallow for at least 30 seconds, and then compared to at least onethreshold. For example, the value of the LES-EEP should be below anormal value threshold, such as 10-20 mmHg, preferably 12-18 mmHg, andmore preferably 15 mmHg, in order for the patient to qualify fortreatment. In another embodiment, a patient's LES-EEP is measured andcollected during resting time, e.g. no swallow for at least 30 seconds,and then compared to a range of pressure values, e.g. to two differentthreshold values. For example, the value of the LES-EEP should be abovea lower threshold, which is indicative of the LES having some basefunctionality, such as 0 mmHg to 3 mmHg or any increment therein andbelow an upper threshold, such as 8 mmHg to 10 mmHg or any incrementtherein.

Another physiological measurement that may be used to select eligiblepatients is the rate of transient LES relaxation events (tLESr).Patients with higher rates of tLESrs which constitute a portion of theiracid exposure time above a predefined threshold may benefit less fromtreatment than patients with lower rates of tLESrs constituting aportion of their acid exposure time above a predefined threshold. In oneembodiment, a patient's tLESr rate is determined over a period of time,such as 24 hours or less. The tLESr rate is determined by recording thenumber and duration of acid exposure events, as described above, andthen calculating the number of acid exposure events shorter than apredefined time period, such as shorter a total time threshold, asdefined above, shorter than 5 minutes, shorter than 10 seconds orshorter than any increment therein, generally referred to as a shortevent. The number of such short events per period is then compared to aninclusion threshold, such as a range of 3-50, preferably 5-20. If thenumber of short events is below the range, the patient may not qualifyfor treatment or may qualify for a different stimulation regimen thatcan be programmed into the stimulator.

Another physiological measurement that may be used to select eligiblepatients is the presence, size or type of hiatal hernia. For example, apatient with certain size (e.g. >2 cm) or type (e.g. Hill grade 4) maybenefit less from this therapy. These patients may require the repair ofthe anatomical defect to receive improved or desirable benefit from thistherapy. In another embodiment, a patient's acid exposure times arerecorded and then compared to the timing of patient's reported refluxsymptoms. The degree of temporal correlation between the acid exposuretimes and reported symptoms is then determined. Patients with a degreeof correlation above a predefined threshold would be eligible fortreatment while those below the predefined threshold would not be.

In another embodiment, it is determined whether a patient maytherapeutically benefit from the electrical stimulation treatmentsystems and methods disclosed herein by temporarily stimulating thepatient for a period of time, such as less than one week, using anon-permanent implanted stimulator to evaluate the patient'sphysiological response to stimulation and predict the patient's likelyphysiological response to a permanent stimulator. In one embodiment, thetemporary stimulation is delivered using a temporary pacing leadendoscopically implanted in the patient's LES and connected to anexternal stimulator, which is either a non-portable system or a portablebattery-operated device. The temporary stimulation system deliversperiodic stimulations over a period of time, from 30 minutes to twoweeks or more, during which the patient's symptoms, acid exposureevents, and physiological response are recorded and correlations betweenthe three are determined. The temporary stimulation data can then beused to determine the likely timings of diurnal GERD events and therequired stimulation parameters to proactively normalize the patient'sLES in advance of the diurnal GERD events, as previously discussed. Oncethe temporary stimulation period is complete, the electrode can beremoved and a decision can be made regarding whether the patient wouldtherapeutically benefit from a permanent implant based, for example, onthe patient's physiological response to the temporary stimulation,improvement in symptoms, normalization of pH levels, and/ornormalization of LES pressure.

In one embodiment, the temporary stimulator is in the shape of a smallcapsule-like device that is self-contained and includes all requiredcomponents for stimulation including a power source or a receiver thatallows power to be received wirelessly from outside the body and one ormore electrodes. The device is adapted to stimulate the LES tissue. Thedevice also includes an anchoring component, such as a hook, corkscrew,rivet, or any other such mechanism, which temporarily connects it to theLES wall. The capsule is implanted through an endoscopic orcatheterization procedure to the LES wall. Such a capsule is expected toremain attached to the LES wall for a period of one day to two weeks orlonger and then detach by itself and leave the body naturally. Furtherthe device can include a sensor for detecting when it is attached to thewall, which will only stimulate when it detects that the device is stillattached to the LES wall. Additionally the device may include wirelesscommunication to allow telemetry and/or commands to be delivered fromoutside the body. The capsule can additionally include pH measurement,manometry measurement or other physiological measurement devices orsensors so that the short term efficacy of the stimulation can be moreeasily evaluated. Additional standard measurements can be made as neededfor obtaining more information.

It should be appreciated that any form of temporary stimulator could beused. For example, a stimulator can include a) a plurality ofimplantable leads adapted to be temporarily implanted into the LEStissue through endoscopy, laparoscopy or other minimally invasivemethods and further adapted to deliver stimulation to the LES, b) ahousing which includes a control unit and circuitry for generatingelectrical stimulation where the housing is adapted to be temporarilyimplantable and/or be integrated with the leads such that the housingitself can deliver stimulation or externally located and wired to theleads without being implantable and/or c) an additional unit capable ofrecording the physiological data, stimulation data, and various patientinputs (symptoms, eating, sleeping events, etc.) and adapted to be usedfor turning stimulation on or off. Optionally, the additional unit iscontrolled by a physician and wirelessly programmable using aphysician's computer system. Optionally, the stimulator can also beconfigured to include sensors or communicate with sensors that measurethe aforementioned physiological measures.

Other approaches for selecting patients based on physiological dataand/or temporary stimulation can also be implemented. It should be clearto person skilled in the art that the above selection methods could beintegrated in various ways to result in an optimal selection ofpatients. For example one integrated method can be used to screenpatients by qualifying candidates according to pH long events, themanometry value of LES-EEP, or the number of short events, or anycombination thereof. Additionally, a combination of the measures can beused such as dividing the total length of long events by the rate ofshort events and comparing this value against a properly adjustedthreshold, such that patients with a ratio above the threshold areincluded and others are excluded. Once qualified, the patient canundergo the permanent implant procedure or undergo the temporarystimulation process to further qualify the patient.

Physician Diagnostic and Programming Systems and Methods

Different patients may require different therapeutic regimens, dependingupon implant depth, anatomical variations, treatment objectives, andseverity of the disease condition. Each patient has a different restinglower esophageal sphincter (LES) pressure and different responses tostimulation (due to expected variability in sphincter muscle conditionand also in the implant location). Furthermore, changes to the patient'sanatomy, for example arising from normal healing after implantation,chronic stimulation or age, can also change the optimal stimulationdosage. Accordingly, it is preferred for a patient to first undergo adiagnostic process to determine whether, and to what extent, the patientcan be treated by one of a plurality of therapeutic processes, asfurther described below. It is also preferred for a patient toperiodically visit a physician to have the efficacy of the stimulationsystem checked, optimized, and possibly reprogrammed, as provided below.

In one embodiment, because the goal is to keep the sphincter at apressure or function which eliminates or greatly reduces the chances foracid exposure, it is unnecessary for the muscle to always have highpressure but, rather, it is desirable to have (1) some average pressuresustained at all times with a certain permitted range of variabilityaround it and a minimal pressure that the sphincter will never be, orwill rarely be, below or (2) some average function sustained at alltimes with a certain permitted range of variability around it and aminimal function that the sphincter will never be, or will rarely be,below or a combination thereof. Continuous non-stop stimulation is notoptimal because the acute response of enhanced pressure may diminishover time due to neuro-muscular tolerance or muscle fatigue.Furthermore, a simple “on-off” regime during which the muscle isstimulated for a first duration and then the stimulation is turned offfor a second duration may be effective; however, different muscleproperties, variations in the patient condition, and variations in theimplant may require a different selection of the “on” and “off” periodsfor each patient and may also require a change in the initial selectionof the “on” and “off” periods over time in the same patient.

In one embodiment, a patient's average pressure (AP) and minimalpressure (MP) is set by conducting a parameter setting test, in which astimulator is controlled by an operator and a manometry measurement ofLES pressure is made. During this test, the operator turns on thestimulation and then observes the LES pressure while keeping thestimulation on until the pressure crosses a first threshold, defined,for example, by AP+(AP−MP). When the observed pressure passes this firstthreshold, the stimulation is either turned off or kept on for anadditional short period of up to 5 minutes and then turned off. Theoperator notes the time when the stimulation is turned off.

The operator continues to observe the pressure and once the pressurereaches MP, the operator turns on the stimulation again and notes thetime. This measurement process continues for several hours, such as 2 to5 hours, so that several stimulation on-off periods can be recorded. Atthe end of the test period, a chronic “on” time is selected to be themedian of the measured “on” periods and a chronic “off” period isselected to be the median of the measured “off” periods. It should beappreciated that the initiation of stimulation, turning off ofstimulation, recordation of time periods, and recordation of LESpressure can be performed automatically, based on a pre-programmed setof threshold values, by a computing device comprising a processor andmemory storing the threshold and control instructions as a set ofprogrammatic instructions.

In another embodiment, a patient's average pressure (AP) and minimalpressure (MP) is set by conducting a parameter setting test, in which astimulator is controlled by an operator and a manometry measurement ofLES pressure is made. During this test, the operator turns on thestimulation, notes the electrode impedance value, and then observes theLES pressure while keeping the stimulation on until the pressure crossesa first threshold, defined, for example, by AP+(AP−MP). When theobserved pressure passes this first threshold, the stimulation is eitherturned off or kept on for an additional short period of up to 5 minutesand then turned off. The operator notes the time when the stimulation isturned off and the electrode impedance value when the stimulation isturned off.

The operator continues to observe the pressure and once the pressurereaches MP, the operator turns on the stimulation again and notes thetime and electrode impedance value. This measurement process continuesfor several hours, such as 2 to 5 hours, so that several stimulationon-off periods can be recorded. Electrode impedance is measured everytime the stimulation is turned “on” or “off”. At the end of the testperiod, a chronic “on” time is selected to be the median of the measuredimpedance value for the “on” periods and a chronic “off” period isselected to be the median of the measured impedance value for the “off”periods. Rather than setting a stimulation device to operate based onfixed time periods, a stimulation device is programmed to turn off andon based upon the measured impedance values, where the device turns onwhen a patient's impedance value approaches the measured mean, median,or any other calculated impedance value for the on periods and turns offwhen a patient's impedance value approaches the measured median, mean,or any other calculated impedance value for the off periods. It shouldbe appreciated that the initiation of stimulation, turning off ofstimulation, recordation of time periods, recordation of electrodeimpedance, and recordation of LES pressure can be performedautomatically, based on a pre-programmed set of threshold values, by acomputing device comprising a processor and memory storing the thresholdand control instructions as a set of programmatic instructions. Itshould be appreciated that, in addition to the above embodiments, apatient's LES pressure may be recorded by conducting a parameter settingtest, in which a stimulator is controlled by an operator and a manometrymeasurement of LES pressure is made. The recorded LES pressures arecompared to a predefined threshold to determine a maximum pressure whichshould preferably not be exceeded. The aforementioned on and off periodsare then set or modified based on this maximum pressure data.

It should be appreciated that the use of impedance values is useful,relative to manometry measurements, if the values of the “on” and “off”periods in the acute phase do not converge to a small range within a fewminutes. It should further be appreciated that other measurements,instead of impedance, can be used, including physical tension sensors(i.e. implantable strain gauge) or sensors of the muscle electricalactivity or sensor of muscle pressure. Furthermore, it should beappreciated that both of the aforementioned tests can be used, and/orcombined, to fix time windows for the “on” and “off” periods and rely onimpedance measurements in order to adapt, modify, or change the timewindows to account for a possible drift in muscle status.

In another embodiment, a programmable impedance tracking parameter,independent of pressure measurements, is used to modulate stimulationtherapy. The impedance tracking parameter can be set to on or off and,when on, measures daily impedance values prior to each stimulationsession. In one embodiment, six measurements are made in successionprior to the scheduled stimulation session. In one embodiment, the siximpedance measurements are taken one every 5 seconds with the finalmeasurement taken one minute prior to stimulation. An average orvariability index is calculated from these measurements by discardingthe high and low measurements and averaging the remaining four.

Based on the measurements taken, the stimulation parameters can bemodified by, in one embodiment, adjusting the amplitude of thestimulation pulse. In one embodiment, the amplitude can be adjusted bymodifying the amplitude of the voltage to maintain a fixed amount ofcurrent (mA). The amplitude change can be bound by a maximum voltage, aminimum voltage, and/or a maximum change allowed for the pulse amplitudewith each stimulation.

In one embodiment, a safety and efficacy check is programmed into theimpedance tracking parameter. If the six measurements are determined tobe inappropriate, stimulation is delayed for 5 minutes, after which timean additional six measurements are taken. Measurements continue to betaken in this manner, delaying stimulation until stable measurements areobtained or until the dose time has expired. The use of the impedancetracking parameter provides more consistent stimulation across allsessions and decreases the requirement for follow-ups, particularlywithin the first 8-12 weeks. An additional benefit of the impedancetracking parameter is that it provides quicker failure detection.

In another embodiment, a doctor makes a determination regarding the LESelectrical stimulation therapy (LES-EST) available to a patient by firstengaging in a process for evaluating a plurality of appropriate dosingvalues for a patient. The evaluation process comprises subjecting apatient to a plurality of pulse sequences and measuring thecorresponding LES pressure.

TABLE 4 Electrical Pulse Pulse Pulse Phase # Stimulation Type FrequencyDuration Amplitude 1 Short Pulse 20 Hz 200 μsec 5 mAmp 2 Short Pulse 20Hz 200 μsec 3 mAmp If #1 reaches ≧20 mmHg 3 Short Pulse 20 Hz 200 μsec 7mAmp If #1 does not reach ≧20 mmHg 4 Short Pulse 20 Hz 200 μsec 10-15mAmp If #3 does not reach ≧20 mmHg 5 Intermediate 20 Hz  3 ms 3-15 mAmpPulse using the same sequence as 1-4 6 Optimal Pulse 20 Hz OptimalOptimal Pulse amplitude

As shown above, each of phases 1-4 is applied for 20-30 minutes with a20-30 minute interval between sessions. The pulse increments can rangefrom 0.1 mAmp to 15 mAmp. The pulse in Phase 6 is intermittently appliedfor 5 hours, during which stimulation is turned on until pressure isgreater than or equal to 20 mmHg for at least 5 minutes (on period) andthen turned off until pressure drops to less than 10 mmHg or patient'sbaseline whichever is higher (off period), and then turned on againuntil it is greater than or equal to 20 mmHg again (on period),repeating thereafter. These on-off sessions continue while the timedurations are recorded. These recorded periods are then used todetermine the optimal duty cycle for the patient during the treatmentphase (patient-specific LESEST). It should be appreciated that, if asubject experiences pain or discomfort for any given stimulationsequence, the pulse amplitude is decreased in 1 mAmp increments untilstimulation is tolerable. Once the effective tolerable setting isestablished, the patient-specific LES-EST is initiated with the definedstimulation parameters, as determined by the parameter setting stagedescribed above. Preferably, the patient-specific LES-EST is checked ata set schedule (every 6 months or once a year) or when a patient startsreporting diurnal GERD symptoms using manometry and the patient-specificLESEST parameters are then modified to achieve ideal LES pressure.

It should be appreciated that the aforementioned diagnostic processesaccount for a plurality of variables that substantially affect treatmentquality, treatment efficacy, and patient compliance, including, but notlimited to, patient's disease condition and the correspondingstimulation energy level and frequency required to achieve a positivetherapeutic effect, patient willingness to manually apply stimulation,and form factor of the stimulation source, among other variables.

The variables generated in the course of the diagnostic processes can beused to automatically program a controller, which may be used to controla stimulator. In one embodiment, a diagnostic terminal executing on aconventional computer generates at least one variable, such asstimulation pulse width, frequency, amplitude, ramp rate, or a dutycycle, that substantially affects treatment quality, treatment efficacy,and patient compliance, including, but not limited to, patient's diseasecondition and the corresponding stimulation energy level and frequencyrequired to achieve a positive therapeutic effect, patient willingnessto manually apply stimulation, and form factor of the stimulationsource, among other variables. The diagnostic terminal is in datacommunication with a controller configuration terminal thatelectronically receives a controller into an interface or wirelesslycommunicates with the controller that is responsible for executing thestimulation parameters. Upon generating the variables, the diagnosticterminal transmits the variables, which are eventually received by thecontroller and saved in an appropriate memory location. The controllerthen uses the variables to control one or more stimulation settings.

In another embodiment, the stimulation parameters are checked by aphysician using a data terminal, such as a laptop, tablet computer,mobile device, or personal computer. As discussed above, data relevantto the efficacy of the stimulation parameters can be wirelessly obtainedfrom the stimulation device memory or from a patient controlledcomputing device, such as a tablet computer, laptop, personal computer,or mobile device. The physician can modify the stimulation parameters inaccordance with the received data and, using the data terminal, issuemodified stimulation parameters to the controller of a stimulator asdescribed above.

In another embodiment, the implantable pulse generator (IPG) isprogrammable via an integrated accelerometer and an external device. Theexternal device acts to send signals to the accelerometer which, inturn, leads to a change in program for the IPG accordingly. In oneembodiment, the external device comprises a battery operated, hand heldvibrator device with at least one user operable button. In oneembodiment, the vibrator device is powered by AAA batteries to lowercost and enhance ease of use. The patient holds the vibrator deviceagainst the skin for a specified period of time, proximate theimplantation location of the IPG, and then presses the button toactivate the device and send vibratory signals to the accelerometer ofthe IPG. In one embodiment, the vibrator device is held over theimplantation area for a period of 15 seconds.

In one embodiment, the vibrator device includes a symptom button(pressed for start and stop of symptoms), a drink button (pressed forstart and stop of drinking, except for water), and a meal button(pressed for start and stop of meals). Pressing the appropriate buttoncauses the vibrator device to transmit a specific vibratory signal, eachwith a different frequency, to the accelerometer of the IPG. Theaccelerometer responds to any vibrations and a microcontrollercontaining firmware algorithms analyzes the accelerometer signal output.After the microcontroller analyzes the effect of the vibratory signal onthe accelerometer signal output, the microcontroller then programs theIPG to provide stimulation targeted toward symptoms or toward a GERDtriggering event.

In another embodiment, the implantable pulse generator (IPG) isprogrammable via patient taps on the skin proximate the implantationlocation of the IPG, wherein the taps are sensed by an integratedaccelerometer. The patterns of the taps are configured to signifysymptoms or GERD triggering events. In one embodiment, one tap signifiesa drink other than water, two taps signifies a meal, and three tapssignifies symptoms, such as heartburn or regurgitation. Theaccelerometer signal leads to a programming of the IPG where saidsignals are based on the number of taps applied to the skin surface bythe patient.

In one embodiment, stimulation is not modified until a predeterminednumber of consistent signals are received by the accelerometer. Forexample, in one embodiment, the accelerometer signal will not lead to areprogram of the IPG until it has received at least seven like signalswithin a 30 minute period for a meal or at least three like signalswithin 30 minutes for symptoms. This system will allow the patient toaddress mild to moderate symptoms while still being able to contact thephysician in the event of more severe symptoms.

Programming of the IPG based on the accelerometer signals via thevibrator device or by tapping is achieved by adjusting parameters of thestimulation, including timing of stimulations. For example, in oneembodiment, if a patient relays heartburn or regurgitation symptoms tothe accelerometer around the same time for at least three of theprevious seven days, an additional stimulation session is added. If, inthe following week, the patient continues to communicate symptoms afterthe addition of a stimulation session, the accelerometer will concludethat the continued symptoms are not GERD or are not addressable bytherapy and will drop the added session. Alternatively, in oneembodiment, if a patient relays symptoms to the accelerometer asdescribed above, the existing stimulation sessions are modified toincrease stimulation strength and/or duration. In another embodiment,extra stimulation sessions can be added in addition to optimizingexisting stimulation sessions. Conversely, if fewer symptoms are relayedto the accelerometer by the patient, the IPG is programmed to dropsimulation sessions or lower stimulation intensity and/or duration.

In one embodiment, vibratory signals transmitted to the accelerometerare stored in internal memory and provide a summary profile of patientsymptoms, drink times, meal times, and sleep times to care providers.The patient only needs to relay a portion, such as a majority, ofsymptoms and GERD triggering events and the system need only save aportion, such as a majority, of events. For example, in one embodiment,for a 45 day period, the system only records and saves 30 events forparticular times of each day (30 lunches, 30 dinners, and 30 eveningsnacks). Besides providing caregivers with a summary profile of patientsymptoms and GERD triggering events, the vibrator device andaccelerometer system can be used as a measure of patient compliance. Forexample, in one embodiment, if a patient is not relaying meal events onthe days he is experiencing symptoms, the patient might not be complyingwith the physician provided therapy.

Exemplary Therapies

The following description is intended to provide examples of how thetherapies, described above, may be specifically implemented. They shouldnot be viewed as limiting the general scope of the inventions describedherein.

Therapy One: Patient Timed and Delivered Stimulation Using a HandheldDevice

In a first therapy, a patient can be effectively therapeutically treatedwith intermittent wireless short bursts of stimulation applied aplurality of times during a day. For example, in one embodiment, apatient can be treated by applying a burst of stimulation for a periodof five minutes or less at a frequency of 5 times or less per day. Inanother embodiment, the stimulation occurs less than 5 times a day for aperiod of 30 minutes or less per stimulation. This stimulation frequencyis effective to treat certain symptoms of a patient, includingdiminishing or eliminating a patient's heartburn, regurgitation or both.

In this treatment method, a patient can be effectively treated by havingthe patient apply an external power source over a predefined area on thepatient's body and manually initiate a stimulation. FIG. 16 is a firstembodiment of a block diagram of certain modules of the presentinvention. In one embodiment, the stimulation system comprises astimulation source 1600 and a microstimulator 1601. As shown in FIG. 16,the stimulation source 1600 comprises a controller 1602, transducer1603, waveform generator 1604, and power source 1605, such as a battery.The stimulation source 1600 directs energy, such as ultrasound or RFenergy, across the patient's skin 1610 and toward a microstimulator 1601that is implanted directly on the site being stimulated. The stimulationsource 1600 can generate a plurality of different pulse widths,amplitudes, frequencies, or combinations thereof, as further describedbelow.

In certain situations, the device may require an energy supply to powerthe implantable pulse generator, but it is difficult or undesirable toinclude an implantable battery that would be wired to the device due tosize limitations, restrictions arising from the implant location, or theneed to decrease device costs. In one embodiment, a rechargeable batteryis wired to the stimulator. The rechargeable battery stores a smalleramount of charge, and therefore can be small in size, but is configuredor adapted to be replenished using wireless transmission of energy.

In another embodiment that requires an implanted device size which iseven smaller than that which is possible with a rechargeable battery andassociated recharging circuit, the device comprises a passive circuitthat receives, in real time, transmitted wireless energy from atransmission source external to the patient. The implanted passivecircuit would control the extraction of the transmitted energy and thedelivery of the energy to the rest of the stimulator device. Theexternal energy transmission device would control the timing ofstimulation and any sensing and/or triggering mechanisms relatedthereto. One limitation to the wireless transmission of energy is theamount of energy that can be wirelessly transmitted in any given timedue, for example, to safety or interference requirements. Such wirelessenergy transmission limitations narrow the applicable stimulationamplitude and waveform that can be applied to the tissue, therebylimiting the clinical application and benefit of such systems.

In another embodiment, the microstimulator comprises a means for storinga charge locally, such as a short-term energy storage component or acapacitor, and an associated trigger mechanism. During an on-off dutycycle for stimulating the microstimulator, the off-time of thestimulation duty cycle can be used to temporarily store a charge,thereby enhancing the maximal amplitude and variety of waveform that canbe applied. The implanted device circuit is configured to control andtime the stimulation in response to energy or control information from acontroller that is external to the patient and communicates wirelesslywith the implanted device. The implanted circuit extracts thetransmitted energy or control information and, in response thereto,shapes the waveform within the off-time of each stimulation cycle usingcomponents such as capacitors, diodes, inductors, transistors andresistors.

The operating characteristics of a capacitor integrated with, or localto, the implanted device will be determined, at least in part, by therequired pulse duration and the ratio of required stimulation pulseamplitude to minimal expected extracted supply current within theimplantable device. The capacitor characteristics will also be afunction of the load impedance. For example, assuming a required pulseduration of 200 μs to be applied every 50 ms and a required amplitude of10 mAmp, the device will need to provide a charge of 2 μC (10 mAmp×200μs). Assuming an impedance of 100 ohms with a voltage of 1 V (10mAmp×100 ohm), then the minimum required capacitor will have a value asapproximated by the following equation:

C=Q/V=2 uC/1V=2 uF

This value will need to be adjusted so that it is not fully dischargedduring stimulation and to compensate for losses within the implantabledevice. For an overall cycle of, for example, 50 ms the theoreticalminimal extracted supply current that can drive the required pulse willbe:

Minimal extracted current=10 mAmp×200 μs/(50 ms−200 μs)=0.04 mAmp

Adjusting for internal losses within the stimulator will yield apractical limit of about 0.1 mAmp or 100 μAmp. Higher available supplycurrents can allow for shorter cycles or longer pulse duration asnecessary and can be extrapolated from the above.

In one embodiment, energy need not be stored between cycles and thepassive circuit responds, in real-time, to the wireless transmission ofenergy. For example, the implanted circuit may initiate a stimulationpulse in response to a stimulation pulse wirelessly sent by the externalenergy transmitting unit, where the energy transmission is above apre-defined time period, is characterized by the intermittent ceasing ofenergy transmission, or is characterized by another combination of“on”-“off” energy signals.

In one embodiment, the stimulation source 1600 directs ultrasonic energyto the microstimulator 1601 which comprises an ultrasonic receiver. Themicrostimulator 1601 is implanted into the area to be stimulated via anendoscope. The microstimulator 1601 can function either as apass-through for energy and stimulation parameters or comprise an energystorage and programmatic memory to deliver short stimulation bursts,using the stored energy, at predetermined time intervals, pursuant tothe programmed memory.

In one embodiment, the stimulation source 1600 directs radio frequency(RF) energy to the microstimulator 1601 which comprises an RF receiver.The microstimulator 1601 is implanted into the area to be stimulated viaan endoscope. The microstimulator 1601 can function either as apass-through for energy and stimulation parameters or comprise an energystorage and programmatic memory to deliver short stimulation bursts,using the stored energy, at predetermined time intervals, pursuant tothe programmed memory.

In one embodiment, the stimulation source 1600 comprises a controller1602, transducer 1603, waveform generator 1604, and power source 1605,such as a battery. Operationally, the controller 1602, via a processorin data communication with a memory storing programmatic instructions,causes the waveform generator 1604 to generate a predefined waveform,having an associated pulse width, amplitude, and frequency, which istransmitted via the transducer 1603 to the endoscopically implantedmicrostimulator 1601. A patient applies the stimulation source 1600intermittently for a short time period, preferably 30 minutes or less,over the microstimulator 1601 site. Where the microstimulator 1601comprises a local memory for storing programmatic instructions, inparticular stimulation parameters and processes, the stimulation source1600 need not comprise a controller and memory for storing suchprogrammatic instructions and may simply transmit a predefined amount ofenergy to the microstimulator.

In another embodiment, referring to FIG. 17, the stimulation source 1700comprises a controller 1702, waveform generator 1704, and power source1705, such as a battery. It wirelessly communicates with, and/ortransfers energy to, a transducer 1703 that is implanted subcutaneously.The subcutaneous transducer 1703 receives the wirelessly transmittedenergy, such as RF or ultrasound, through the patient's skin surface andtransmits it, via a wired or wireless connection, to an endoscopicallyimplanted microstimulator 1701. Operationally, the controller 1702, viaa processor in data communication with a memory storing programmaticinstructions, causes the waveform generator 1704 to generate apredefined waveform, having an associated pulse width, amplitude, andfrequency, which is transmitted wirelessly into the patient'ssubcutaneous region and into the transducer 1703, which furthertransmits the energy to the microstimulator 1701. A patient applies thestimulation source 1700 intermittently for a short time period,preferably thirty minutes or less, over the transducer site. Where themicrostimulator 1701 comprises a local memory for storing programmaticinstructions, in particular stimulation parameters and processes, thestimulation source 1700 need not comprise a controller and memory forstoring such programmatic instructions and may simply transmit apredefined amount of energy to the transducer 1703 and, thus, to themicrostimulator 1701. It should be appreciated that, regardless of thetype, the stimulation source 1700 can be integrated into a plurality ofdifferent housings, including a miniature flashlight, cell phone case,or smart card. In one embodiment, the subcutaneous transducer 1703receives lower frequency electro-magnetic energy and commands from thestimulation source 1700 and converts the energy into high frequency RFenergy. The frequency conversion will be less efficient than direct RFtransmission but the use of the subcutaneous transducer will assist ineliminating heating issues. In addition, the subcutaneous transducer canalso be used as a simple energy storage unit. In another embodiment, thesubcutaneous transducer 1703 receives lower frequency electro-magneticenergy and commands from the stimulation source 1700 and converts theenergy into ultrasound energy.

In another embodiment, referring to FIG. 18, a patient is treated bylaparoscopically implanting a plurality of electrodes or electrodes 1801(within the anatomical area to be stimulated) in wired communicationwith a transducer 1803 (comprising an antenna) proximate to the skinsurface. The transducer 1803 wirelessly communicates with an externalenergy source 1800 (comprising a controller 1802, waveform generator1804, and power source 1805, such as a battery) across the surface ofthe patient's skin 1810. The external energy source 1800 can be appliedto the stimulation site by a patient, as described above. With closeenergy source application, radio frequency, ultrasound, orinductive/magnetic energies can be used.

As further discussed below, the stimulation source 1600, 1700, 1800 caninitiate or terminate stimulation, when properly placed over theappropriate site, based on any of a plurality of triggers, includingmanually by a patient, patient activity, or other sensed patient states.The stimulation source 1600, 1700, 1800 can generate a plurality ofdifferent pulse widths, amplitudes, frequencies, or combinationsthereof, as further described below.

Therapy Two: Controller Timed and Delivered Stimulation

In a second therapy, a patient may not be effectively therapeuticallytreated with intermittent wireless short bursts of stimulation applied aplurality of times during a day. Rather, a patient requires bursts ofstimulation for a period greater than a predefined period of time, orfor a frequency of more than a predefined number of times per day.Accordingly, a patient is subjected to stimulation that is initiated,effectuated, or otherwise triggered by a programmed controller. Thismore frequent, or continuous, stimulation is effective to treat certainsymptoms of a patient, including treatment of heartburn orregurgitation, or reaching a predetermined LES pressure, muscle tensionor electrode impedance.

In this treatment method, a patient can be effectively treated by aplurality of embodiments, including:

1) Referring to FIG. 19, endoscopically implanting a microstimulator1901 (having a receiver and placed within the anatomical area to bestimulated) in wireless or wired communication with a subcutaneouslyimplanted transducer 1903 that, in turn, wirelessly communicates with atransducer 1906 (comprising at least one antenna and an adhesivesurface) applied to the patient's skin surface 1910 which is wired to,and receives signals from, a stimulator source 1900 (comprising acontroller 1902, waveform generator 1904, and power source 1905, such asa battery). The controller 1902 can be programmed to initiate orterminate stimulation based on a plurality of patient-specific triggers,such as pH level, LES pressure, fasting state, eating state, sleepingstate, physical incline, or patient activity state, among other triggersas further described below. The stimulation source 1900 can generate andtransmit radio frequency or ultrasound energy and can generate aplurality of different pulse widths, amplitudes, frequencies, orcombinations thereof, as further described below. In one embodiment, theradio frequency or ultrasound pulse is designed to operate over awireless distance of 6 inches or less, through the human body, with amaximum pulse amplitude of 10 mAmp and a maximum pulse width of 10 msec.It should be appreciated that if one parameter is lowered, such as thewireless distance (lowering it to one inch), another parameter can bemodified accordingly, such as the amplitude (increasing it to 30 mAmp).

2) Referring to FIG. 20, endoscopically implanting a microstimulator2001 (having a receiver and placed within the anatomical area to bestimulated) in wireless communication with a stimulator source 2000(comprising a controller 2002, transducer 2003, waveform generator 2004,and power source 2005, such as a battery and which is held against apatient's skin 2010 over the microstimulator site, such as with straps,adhesives, garments, or bindings). The controller 2002 can be programmedto initiate or terminate stimulation based on a plurality ofpatient-specific triggers, such as pH level, LES pressure, fastingstate, eating state, sleeping state, physical incline, or patientactivity state, among other triggers as further described below. Thestimulation source 2000 can generate and transmit radio frequency orultrasound energy and can generate a plurality of different pulsewidths, amplitudes, frequencies, or combinations thereof, as furtherdescribed below. In one embodiment, the radio frequency or ultrasoundpulse is designed to operate over a wireless distance of 6 inches orless, through the human body, with a maximum pulse amplitude of 10 mAmpand a maximum pulse width of 10 msec. It should be appreciated that ifone parameter is lowered, such as the wireless distance (lowering it toone inch), another parameter can be modified accordingly, such as theamplitude (increasing it to 30 mAmp).

3) Referring to FIG. 21, endoscopically implanting a microstimulator2101 (having a receiver and placed within the anatomical area to bestimulated) in wireless communication with a relay device 2106 worn overthe stimulation site 2110 that is in wired communication with anexternal stimulator 2100, in wireless communication with an implantedadapter 2107 that is in wireless communication with an externalstimulator 2100, or in wireless communication with an implantedtransducer 2108 that is in wired communication, via an electrode, to animplanted stimulator 2109. The stimulator 2100 (comprising a controller2102, transducer 2103, waveform generator 2104, and power source 2105,such as a battery) can be programmed to initiate or terminatestimulation based on a plurality of patient-specific triggers, such aspH level, LES pressure, fasting state, eating state, sleeping state,physical incline, or patient activity state, among other triggers asfurther described below. The stimulation source 2100 can generate andtransmit radio frequency or ultrasound energy and can generate aplurality of different pulse widths, amplitudes, frequencies, orcombinations thereof, as further described below. In one embodiment, theradio frequency or ultrasound pulse is designed to operate over awireless distance of 6 inches or less, through the human body, with amaximum pulse amplitude of 10 mA and a maximum pulse width of 10 msec.It should be appreciated that if one parameter is lowered, such as thewireless distance (lowering it to one inch), another parameter can bemodified accordingly, such as the amplitude (increasing it to 30 mAmp).

4) Referring to FIG. 22, laparoscopically implanting a plurality ofelectrodes 2201 (within the anatomical area to be stimulated) in wiredcommunication with an implanted stimulator 2200 (comprising a primarycell that provides energy and a memory with programmatic instructionsfor defining appropriate stimulation parameters) which can be programmedto generate stimulation either continuously or periodically based on apredefined program or based on patient-specific triggers, such as pHlevel, LES pressure, LES impedance, fasting state, eating state,sleeping state, physical incline, or patient activity state, among othertriggers as further described below. The stimulator 2200 may alsowirelessly receive control data or information from an external device,which may be controlled, at least in part, by a physician or patient.The stimulator 2200 can generate a plurality of different pulse widths,amplitudes, frequencies, or combinations thereof, described above.

5) Referring to FIG. 23, laparoscopically implanting a plurality ofelectrodes 2301 (within the anatomical area to be stimulated) in wiredcommunication with a subcutaneously implanted transducer 2302 that, inturn, wirelessly communicates with a stimulator source or a transducer2303 (comprising at least one antenna and an adhesive surface) appliedto the patient's skin surface 2310 which is wired to, and receivessignals from, a stimulator source 2300 (comprising a controller 2304,waveform generator 2305, and power source 2306, such as a battery). Thecontroller 2304 can be programmed to initiate or terminate stimulationbased on a plurality of patient-specific triggers, such as pH level, LESpressure, fasting state, eating state, sleeping state, physical incline,or patient activity state, among other triggers as further describedbelow. The stimulation source 2300 can generate and transmit radiofrequency or ultrasound energy and can generate a plurality of differentpulse widths, amplitudes, frequencies, or combinations thereof, asfurther described below.

It should be appreciated that, while the disclosed system can use RF,inductive coupling, magnetic coupling or ultrasound, in one embodiment,the system can combine the use of RF inductive coupling, magneticcoupling, and ultrasound to take best advantage of transmissionefficiencies in various media. In one embodiment, the externalstimulator source generates RF waveforms, which wirelessly transmits RFenergy to an intermediary receiver, that can be implanted subcutaneouslyand that converts the received RF energy into an ultrasound waveform.The intermediary receiver has an RF receiver, an ultrasound waveformgenerator, and an ultrasound transmitter. In another embodiment, thedevice comprises a means for storing a charge locally, such as ashort-term energy storage component, such as a capacitor, and anassociated trigger mechanism, as described above.

It should further be appreciated that the microstimulator (or, where alaparoscopically implanted stimulation electrode and stimulator areused, the stimulator) can locally store energy, be used with RF or US,and rely on an external device for stimulation control and/or energyrecharge. Specifically, the microstimulator can comprise a means forstoring a charge locally, such as a capacitor. It should further beappreciated that the anatomical region to be stimulated, such as theLES, areas within 2 cm of the LES, the esophagus, or the UES, may bestimulated using a plurality of microstimulators or electrodes,including an array of microstimulators or electrodes affixed to a meshor other substrate. It should further be appreciated the microstimulatoror implanted stimulator can store enough energy to function as a backup,or otherwise fill in gaps in energy transfer from an external sourcewhen, for example, wireless transmission coupling is interrupted orinefficient. In another embodiment, the microstimulator or implantedstimulator receives an energy stream from an external stimulator and, inreal-time, forms the requisite waveform based on parameters encoded in awireless control stream or embedded in the energy stream. In anotherembodiment, the microstimulator or implanted stimulator receives apre-formed waveform from an external stimulator.

As discussed above, the endoscopic therapeutic treatments are part ofthe diagnosis process in which a microstimulator is endoscopicallyimplanted and used in combination with an external device for an initialperiod. Data is gathered regarding frequency of stimulation required,amount of energy required, and other factors. A patient then receives alaparoscopically implanted permanent system operating in accordance withthe gathered data.

Exemplary Use No. 1

In one embodiment, patients with diagnosis of GERD responsive to PPI,increase esophageal acid on 24 h pH monitoring off GERD medications,basal LES pressures ≧5 mm Hg, hiatal hernia <2 cm and esophagitis ≦LAGrade B had a stimulator placed endoscopically in the LES by creating a3 cm submucosal tunnel. The stimulator was secured to the esophagusmuscularis or serosa. Electrical stimulation (EST) was delivered 6-12hours post-implant per following protocols 1) Short-pulse (SP) 200 μsec,20 Hz, 10 mAmp; if no response in LES pressure increase to 15 mAmp; ifincrease in LES pressure decrease to 5 mAmp and 2) Intermediate-pulse(IP) 3 msec, 20 Hz, 5 mAmp for 20 minutes; if no response, increase to10 mAmp. Each session of EST lasted 20 minutes and was followed by awashout period of 20 minutes or time needed for LES pressure to returnto baseline, whichever was longer. High-resolution manometry wasperformed using standard protocol pre-, during and post-stimulation.Symptoms of heartburn, chest pain, abdominal pain and dysphagia pre-,during and post-stimulation were also recorded. Continuous cardiacmonitoring was performed during and after the stimulation to look forany adverse cardiac events associated with EST.

Three patients underwent successful stimulator implantation. One patientwas stimulated using 200 μsec, 20 Hz, 3 mAmp (SP 3) and had asignificant increase in the LES pressure (Baseline=5.7 mm Hg;post-stimulation=42 mm Hg). As shown in FIGS. 24-28, patients had asignificant increase in the LES pressure with all sessions of EST (Table5). There was no effect on swallow induced relaxation and improvement inpost-swallowing LES pressure augmentation with EST. There were noadverse EST related symptoms or any cardiac rhythm abnormalities.

TABLE 5 EST Protocol Median LES pressure (mmHg) Pre- Post- StimulationStimulation Stimulation SP-10 mAmp 8.1 25.3 17.9 SP-5 mAmp 9.7 37.7 17.8IP-5 mAmp 6.5 26.0 29.2

Accordingly, in patients with GERD, EST results in significant increasein LES pressure without affecting patient swallow function or inducingany adverse symptoms or cardiac rhythm disturbances. EST delivered via awired or wireless electrical stimulator offers a novel therapy topatients with GERD.

Exemplary Use No. 2

In one embodiment, a patient with diagnosis of GERD has a baseline LESpressure of 4-6 mmHg and impedance was about 320 ohms. A stimulationhaving a pulse of 200 μs and 5 mAmp was applied. After 15 minutes, asustained LES tone of 25-35 mmHg was observed, which remained high forover 90 minutes after stopping stimulation. After 3 hours, the LESpressure returned to baseline. This patient was than treated using apatient specific stimulation protocol of 200 μs pulse, 5 mAmp amplitude,20 Hz frequency, an ON phase of 20 minutes and an OFF phase of 2 hours.His LES was restored to normal function and his GERD was controlled.

Exemplary Use No. 3

In one embodiment, a patient with diagnosis of GERD has a baseline LESpressure of 4-6 mmHg and impedance was about 320 ohms. A stimulationhaving a pulse of 200 μs and 10 mAmp was applied. After 15 minutes, asustained LES tone of 25-35 mmHg was observed. The patient wasinstructed to engage in a wet swallow. The patient engaged in a wetswallow, while stimulation was being applied, without feeling anysubstantive inhibition of the swallow function. This patient was thentreated using a patient specific stimulation protocol of 200 μs pulse, 5mAmp amplitude, 20 Hz frequency, an ON phase of 20 minutes and an OFFphase of 2 hours. His LES was restored to normal function and his GERDwas controlled. Optionally, a pressure sensor was implanted in the LESand used to terminate the ON phase when a sustained LES pressure ofgreater than 20 mmHg for 5 minutes was achieved and used to terminatethe OFF phase when a sustained LES pressure reaching 10 mmHg or thepatient's baseline, whichever is higher, was achieved.

Exemplary Use No. 4

In one embodiment, patients are subjected to a series of diagnostictests to determine a plurality of therapeutic stimulation parameters andto select stimulation parameters with the lowest average charge which isstill able to elicit a pressure response in the range of at least 15-20mmHg sustained for at least 5 minutes as measured in manometry. Thediagnostic tests include subjecting patients to a series of stimulationsequences, as provided in the table below:

TABLE 6 Stimulation Sequence Settings Electrical Pulse Pulse PulseSequence # Stimulation Type Frequency Duration Amplitude 1High-Frequency 20 Hz 200 μsec 5 mAmp 2 (only if #1 does High-Frequency20 Hz 200 μsec 10-15 mAmp not reach 20 (preferably mmHg or invoke a 10mAmp) sufficiently positive response) 3 (only if #2 does Mid-Frequency20 Hz 3 ms 5-15 mAmp not reach 20 (preferably mmHg or invoke a 10 mAmp)sufficiently positive response) 4 (only if #3 does Mid-Frequency 20 Hz 3ms 5-15 mAmp not reach 20 mmHg or invoke a sufficiently positiveresponse) 5 (only if #4 does Low-frequency 6 cycles/min 375 ms 5 mAmpnot reach 20 mmHg or invoke a sufficiently positive response) 6 (only if#5 does Low-frequency 6 cycles/min 375 ms 5-15 mAmp not reach 20 mmHg)

Each selected stimulation parameter is applied for 5 hours during whichstimulation is turned on until pressure is greater than or equal to 20mmHg for at least 5 minutes (or until the time of duration reaches 60minutes) and then stimulation is turned off until the pressure drops toless than 10 mmHg, or the patient's baseline, whichever is higher.Stimulation is then turned on again until reaching greater than or equalto 20 mmHg again for at least 5 minutes. This on-off process continueswhile the time duration between each on-off cycle is recorded. If thepatient experiences pain or discomfort for any given stimulationsequence, the pulse amplitude is decreased in 1 mAmp increments untilstimulation is tolerable. Once the tolerable setting is established, thestimulation period is re-initiated. Optionally, there is a washoutperiod between sequences to remove any residual effect from theapplication of a prior sequence. That washout period can be equal to onehour or until LES pressure returns to the patient's baseline, whicheveris longer. Optionally, continuous manometry is performed during thepost-stimulation period to assess any delayed effect from a failedsequence or to measure the duration of effect from a successfulsequence.

During the last two hours of the diagnostic session, stimulation isturned “on” and “off” at fixed durations based on the measured valuesrecorded in the first part of the test. Impedance measurements areperformed periodically during this phase using an external impedancemeasurement device or by measuring the resulting voltage waveform fromstimulation using a floating oscilloscope.

Optionally, a second dosing evaluation process is performed building onthe sequence results as performed above. In one embodiment, a patient'sbaseline LES pressure is evaluated over a 20 minute period. Simulationis applied for 125% of the on time period, as determined from the firstset of sequence measurements. Stimulation is then stopped for 75% of theoff time period, as determined from the first set of sequencemeasurements, or until LES pressure falls below 10 mmHg or baseline,whichever is higher. Restart stimulation for 125% of the on time periodand monitor LES pressure. If LES pressure does not reach 20 mmHg, thencontinue stimulation for up to 150% of the on time period or untilpressure reaches 20 mmHg (whichever comes first). Repeat the off timeperiod and continue cycling between the prior on time period and offtime period until achieving 6 hours of LES pressure above 10 mmHg.Conduct esophageal manometry with wet swallows post stimulationsequence.

Exemplary Use No. 5

In one embodiment, patients are subjected to a series of diagnostictests to determine a plurality of therapeutic stimulation parameters andto select stimulation parameters with the lowest average charge which isstill able to elicit a pressure response in the range of at least 15-20mmHg sustained for at least 5 minutes as measured in manometry. Thediagnostic tests include subjecting patients to a series of stimulationsequences, as provided in the table below:

TABLE 7 Electrical Pulse Pulse Pulse Stimulation Sequence # StimulationType Frequency Duration Amplitude Duration 1 Baseline  0 Hz  0 μsec 0mAmp  0 minutes 2 High-Frequency 20 Hz 200 μsec 5 mAmp 30 minutes 3(only if #2 does High-Frequency 20 Hz 200 μsec 10-15 mAmp 60 minutes notreach 20 (preferably mmHg or invoke a 5 mAmp) sufficiently positiveresponse) 4 (only if #3 does High-Frequency 20 Hz 200 μsec 10 mAmp 30minutes not reach 20 mmHg or invoke a sufficiently positive response) 5(only if #4 does High-Frequency 20 Hz 200 μsec 5-15 mAmp 60 minutes notreach 20 (preferably mmHg or invoke a 10 mAmp) sufficiently positiveresponse) 6 (only if #5 does High-Frequency 20 Hz 200 μsec 15 mAmp 30minutes not reach 20 mmHg or invoke a sufficiently positive response) 7(only if #6 does High-Frequency 20 Hz 200 μsec 15 mAmp 60 minutes notreach 20 mmHg)

Stimulation is turned on until pressure is greater than or equal to 20mmHg for at least 5 minutes (or until the list time duration is reached)and then stimulation is turned off until the pressure drops to less than10 mmHg, or the patient's baseline, whichever is higher. Stimulation isthen turned on again until reaching greater than or equal to 20 mmHgagain for at least 5 minutes. This on-off process continues while thetime duration between each on-off cycle is recorded. If the patientexperiences pain or discomfort for any given stimulation sequence, thepulse amplitude is decreased in 1 mAmp increments until stimulation istolerable. Once the tolerable setting is established, the stimulationperiod is re-initiated.

Optionally, there is a washout period between sequences to remove anyresidual effect from the application of a prior sequence. That washoutperiod can be equal to one hour or until LES pressure returns to thepatient's baseline, whichever is longer. Optionally, continuousmanometry is performed during the post-stimulation period to assess anydelayed effect from a failed sequence or to measure the duration ofeffect from a successful sequence. Optionally, continuous manometry isperformed during the post-stimulation period from the successfulsequence to determine the duration of the effect, that is, until the LESpressure is below 10 mm Hg or reaches baseline, whichever is higher.

The stimulation sequences listed above may be repeated, if no success isachieved, except using a 3 msec dose instead of the 200 μsec dose.

Optionally, a second dosing evaluation process is performed building onthe sequence results as performed above. In one embodiment, a patient'sbaseline LES pressure is evaluated over a 20 minute period. Simulationis applied for 125% of the on time period, as determined from the firstset of sequence measurements. Stimulation is then stopped for 75% of theoff time period, as determined from the first set of sequencemeasurements, or until LES pressure falls below 10 mmHg or baseline,whichever is higher. Stimulation is restarted for 125% of the on timeperiod and LES pressure is monitored. If LES pressure does not reach 20mmHg, then continue stimulation for up to 150% of the on time period oruntil pressure reaches 20 mmHg (whichever comes first). Repeat the offtime period and continue cycling between the prior on time period andoff time period until achieving 6 hours of LES pressure above 10 mmHg.Conduct esophageal manometry with wet swallows post stimulationsequence. Additional stimulation measurements can be made, includingbaseline manometry with wet swallows, repeating successful sequences foran extended period, such as 12 hours, or manometry measurements with wetswallows after conducting a successful stimulation sequence.

Exemplary Use No. 6

In one embodiment, 10 patients (9 females, 1 male mean age 52.6 years,range-40-60 years) with symptoms of GERD responsive to PPI's, lowresting LES pressure and abnormal 24-hr intraesophageal pH test wereenrolled. All had symptoms of heartburn and/or regurgitation for atleast 3 months, which was responsive to therapy with proton pumpinhibitors (PPI's). Preoperative evaluation included an upper GIendoscopy, esophageal manometry and ambulatory 24-hr esophageal pHrecording. To be included, the patient's resting LESP had to be 5-15mmHg, and the intraesophageal pH had to be less than four more than 5%of the time. Patients with hiatal hernia >3 cm, erosive esophagitis moresevere than Los Angeles grade C, Barretts esophagus or non-GERD relatedesophageal disease were excluded.

Bipolar stitch electrodes were placed longitudinally in the LES duringan elective laparoscopic surgery, secured by a clip and exteriorizedthrough the abdominal wall. It consisted of two platinum-iridiumelectrodes with an exposed length of 10 mm. They were implantedlongitudinally in the right and left lateral aspects the LES and securedby a clip. The electrode was then exteriorized through the laparoscopicport in the abdominal wall in the left upper quadrant and connected to amacrostimulator.

Following recovery, an external pulse generator delivered 2 types ofstimulation for periods of 30 minutes: 1) low energy stimulation; pulsewidth of 200 μsec, frequency of 20 Hz amplitude and current of 5 to 15mA (current was increased up to 15 mA if LESP was less than 15 mmHg),and 2) high energy stimulation; pulse width of 375 msec, frequency of 6cpm and amplitude 5 mA. Resting LESP, amplitude of esophagealcontractions and residual LESP in response to swallows were assessedbefore and after stimulation. Symptoms of chest pain, abdominal pain anddysphagia were recorded before, during and after stimulation and 7-daysafter stimulation. Continuous cardiac monitoring was performed duringand after stimulation.

The high frequency, low energy stimulation was delivered as square-wavepulses with a width of 200 microseconds at a frequency of 20 Hz and acurrent of 5-15 mA. If LESP did not increase to over 15 mmHg using the 5mA stimulus, the current was gradually increased up to 15 mA. The lowfrequency, high energy stimulation was delivered as square-wave pulsewith a width of 375 milliseconds at a frequency of 6 CPM and current of5 mA. The current was not varied during low frequency stimulation.

If resting LESP rose above 15 mmHg during ES, the stimulus wasterminated and LESP was allowed to return to its pre-stimulationbaseline. A different stimulation was given when LESP returned tobaseline. Stimulations were given in random order, with patients unawareof the type or timing of its delivery (frequent checks of impedance weremixed with stimulation). Five water swallows were given before and aftertermination of each session of ES. All studies were done undercontinuous cardiac monitoring, and patients were supervised closely.Patients were instructed to report any unusual symptom, and inparticular dysphagia, palpitations, and chest/abdominal pain.

Nine subjects received high frequency, low energy and four subjectsreceived low frequency, high energy stimulation. Both types ofstimulation significantly increased resting LESP: from 8.6 mmHg 95%, CI4.1-13.1 to 16.6 mmHg, 95% CI 10.8-19.2, p<0.001 with low energystimulation and from 9.2 mmHg 95% CI 2.0-16.3 to 16.5 mmHg, 95% CI2.7-30.1, p=0.03 with high energy stimulation. Neither type ofstimulation affected the amplitude of esophageal peristalsis or residualLESP. No subject complained of dysphagia. One subject had retrosternaldiscomfort with stimulation at 15 mA that was not experienced withstimulation at 13 mA. There were no adverse events or any cardiac rhythmabnormalities with either type of stimulation.

With respect to high frequency, low energy stimulation, there was aconsistent increase in resting LESP in all subjects, observed within 15minutes of initiating ES, and increased further before the end ofstimulation. High frequency, low energy stimulation had no effect on theamplitudes of esophageal contractions or residual LESP in response to 5cc water swallows. One subject had chest discomfort when the stimulationcurrent was increased to 15 mA, but resolved when the current wasdecreases to 13 mA.

With respect to low frequency, high energy stimulation, resting LESPconsistently increased during stimulation. It had no effect on theamplitudes of peristaltic pressure waves in the smooth muscle esophagusor residual LESP produced by 5 cc water swallows. No abnormalities ofcardiac or esophageal function were seen, and no adverse events occurredwith either type of stimulation.

Both types of stimulation, high and low energy stimulation, caused aconsistent and significant increase in LES pressure. Importantly, bothLES relaxation and esophageal contractile activity in response to wetswallows were not affected, indicating that the integrity of theneuromuscular reflex pathways activated by swallows is maintained duringstimulation. Stimulation was well tolerated. No patient reporteddysphagia. Only one patient reported chest discomfort, with amplitude of15 mA, that was not experienced when current was reduced to 13 mA. Therewas no evidence of cardiac adverse effects in any of the patients.Accordingly, short-term stimulation of the LES in patients with GERDsignificantly increases resting LESP without affecting esophagealperistalsis or LES relaxation.

Exemplary Use No. 7

Six patients with GERD resistant to medical therapy and documented by pHtesting underwent electrode implantation in the LES using laparoscopy.All patients had LES pressures in the range of 5-15 mm Hg. Amacrostimulator was placed in the subcutaneous pocket using steriletechniques. Within 24 hours after the implant, LES electricalstimulation therapy was started using 215 μsec pulse at 3 mAmp and 20Hz. For certain patients, the macrostimulator comprised anaccelerometer/inclinometer which was used to program the delivery ofstimulation twice daily, once every 12 hours, and then increased to 3times daily, once every 8 hours.

The LES electrical stimulation therapy resulted in significantimprovement and normalization of LES pressure as measured byhigh-resolution manometry and clinically significant decreases inesophageal acid as measured by 24 hour pH testing. All patients haddecreases in symptoms measured by patient symptom diaries andimprovements in health related quality of life measured by a HealthRelated Quality of Life survey, short form 12 (GERD HRQL). All patientswere successfully taken off proton pump inhibitors medications, nor didthe patients use the PPIs on an as-needed basis. None of the patientshad treatment related symptoms or adverse events. All patientsmaintained a normal swallow function.

Referring to FIGS. 24 to 28, the treatment methodologies disclosedherein provide for a sustained improvement in patient LES pressure 2405,a decrease in esophageal acid exposure, and decrease in reportedsymptoms. Relative to a baseline pressure 2410, patient LES pressure canachieve a greater than 2× increase during stimulation 2415 relative tobaseline 2410 and can still retain an elevated pressure, relative tobaseline 2410, after stimulation is terminated 2420.

Additionally, as shown in FIG. 25, a patient's LES pressure can bereliably maintained 2515 within a normal pressure range, 15-25 mmHg, forweeks 2505 after LES stimulation is initiated. As a result, a patient'sesophageal acid exposure 2615 can be brought within a normal pH rangewithin one week after initiating treatment and maintained for severalweeks thereafter 2605. Similarly, a patient's adverse symptoms,associated with GERD, 2715 can be brought within a normal range, asmeasured by GERD HRQL evaluations, within one week after initiatingtreatment and maintained for several weeks thereafter 2705. The benefitsof the present therapy can also be obtained within hours afterinitiating and terminating stimulation. As shown in FIG. 28, relative toa pre-stimulation baseline 2820, a patient's LES pressure can bereliably maintained 2815 within a normal pressure range for hours 2805after LES stimulation is terminated 2830.

Exemplary Use No. 7

In one embodiment, the system for treating GERD comprises at least oneelectrode positioned proximate the LES, such as a region that is 3 cmabove and 3 cm below the LES, a waveform generator operably coupled tosaid at least one electrode, and a controller configured to electricallystimulate the LES. The system operates using a combination of one ormore of the following operational ranges: a) a pulse train of 3-8 mA, b)pulse trains are applied for a stimulation period, or on period, of 5-60minutes, b) the device is operated with 3 to 24 stimulations per day,with off periods in between each of the stimulations, c) a pulse trainhas a frequency of 10 Hz to 200 Hz, d) a pulse is 100-1000 usec, e) apulse train is less than 8 mA and extends for a period of time that islonger than 10 minutes, and f) a stimulation comprises pulse trains thatare less than 3 mA and the device is operated with 12 or more suchstimulations per day, with off periods in between each of thestimulations.

Using such a system and the above listed combinations of operationalranges, one or more of the following therapies can be effectivelyimplemented: a) treatment of GERD, b) treatment of nocturnal GERD, c)treatment of diurnal GERD, d) treatment of tLESR, e) treatment of GERDwithout affecting LES pressure, f) modification of esophageal acidexposure without affecting a patient's LES pressure or tone, g)treatment of GERD symptoms without affecting acid exposure or pressure,h) reduce pH without completely closing the LES, i) stimulate the LESwhile not inhibiting physiological LES relaxation, j) modulate LESpressure without completely closing the LES, and/or k) minimizeinappropriate relaxations, such as reflux, while allowing appropriaterelaxations associated with a patient's vomiting, swallowing, orburping. In the course of implementing one more of the above listedtherapies: a patient's LES pressure or tone may be increased duringstimulation, b) a patient's LES pressure or tone may be increased duringstimulation and then maintained in an increased state after stimulationceases, c) a patient's LES pressure or tone may be increased only afterstimulation ceases and not during stimulation, d) the system may operatewithout using, or even requiring the presence of, any sensing system tosense a patient's swallow of a bolus of food or liquid, and e) thesystem may stimulate a patient's LES even while a patient is engaging aswallow.

Methods for Treating GERD and Preventing Weight Gain

The present specification is also directed toward methods and systemsfor treating GERD, nocturnal GERD, diurnal GERD, or tLESR by implantingan electrical stimulation device and operating the stimulation device tostimulate the patient's LES in a manner that induces within the patienta sense of satiety and a desire to eat food more slowly. Theindividual's satiety sensation with treatment is accelerated whenmeasured against the same individual's sense of satiety in the absenceof any electrical stimulation. Accelerating an individual's sense ofsatiety results in the individual eating less food and thereforedecreases the likelihood of weight gain associated with successful GERDtherapy.

It should be appreciated that the systems and methods described hereincan be used with a plurality of different devices, including thoseelectrical stimulation devices disclosed in the various patents andpatent applications incorporated above.

FIG. 29 is a flowchart detailing one embodiment of a method of treatingGERD and simultaneously increasing satiety in a patient. Referring toFIG. 29, a patient has an electrical stimulation device, in the form ofmacrostimulator or microstimulator, implanted 2900 proximate thepatient's LES. The electrical stimulation device is then programmed 2905in accordance with one of a plurality of different stimulation protocolsas described above. It should be appreciated that the electricalstimulation methods used to program the stimulation device may includethose methods disclosed in U.S. patent application Ser. No. 13/041,063,filed on Mar. 4, 2011, which is incorporated herein by reference.

The implanted device is then operated 2910 in accordance with the chosenprotocol. The effectiveness of the stimulation methodology is thenevaluated 2915 to determine a) if it sufficiently minimizes oreliminates the adverse symptoms associated with the patient's GERD,nocturnal GERD, diurnal GERD, and/or tLESR condition and b) if thepatient's sense of satiety is increased or accelerated, therebymoderating or decreasing the patient's food intake relative to asituation where the patient is undergoing no stimulation of the LES. Inaddition, the above conditions should be met without causing any otheradverse effects.

If the chosen stimulation method a) sufficiently minimizes or eliminatesthe adverse symptoms associated with the patient's GERD, nocturnal GERD,diurnal GERD, and/or tLESR condition and b) increases or accelerates thepatient's sense of satiety relative to a situation where the patient isnot being stimulated 2920, then the stimulation protocol is maintained2925. If, however, the chosen stimulation method a) does notsufficiently minimize or eliminate the adverse symptoms associated withthe patient's GERD, nocturnal GERD, diurnal GERD, and/or tLESRcondition, b) does not increase or accelerate the patient's sense ofsatiety relative to a situation where the patient is not beingstimulated, or c) causes other adverse symptoms or conditions, such asdysphagia, 2930, then the stimulation protocol is modified 2935.Modification of the stimulation protocol is continued 2940 until thepatient's GERD symptoms have been sufficiently minimized and satiety hasbeen increased or accelerated without causing other adverse symptoms.

In another embodiment, the implanted device is implanted in a locationto effectuate both the stimulation of the LES and modulate the funduspressure. The fundus typically relaxes after initial food intake to keepgastric pressure low. This mechanism is called “receptive relaxation”.In one embodiment, the implanted device is configured such that theapplied electrical stimulation directly or, indirectly via LESstimulation, interferes with this receptive relaxation and results inhigher fundus pressure which, in turn, causes the patient to eat moreslowly and feel satiety faster. An implanted device can therefore beimplanted in a position, location or configuration that assists in themodulation of the neural system in a manner that helps control funduspressure or gastric pressure.

In another embodiment, the implanted device is implanted in a locationwithin the gastrointestinal tract, and particularly within 2 cm of theLES, to cause a patient to eat more slowly and feel satiety faster, evenif the implanted device is not operated to treat GERD, diurnal GERD,nocturnal GERD or tLESR. More specifically, the electrical stimulationmethods disclosed herein and incorporated by reference may be used totreat obesity, induce weight loss, or suppress weight gain in patientswho do not suffer from GERD, diurnal GERD, nocturnal GERD, or tLESR. Animplanted device can therefore be implanted in a position, location orconfiguration that assists in the modulation of the neural system in amanner that helps control fundus pressure or gastric pressure andthereby also helps modulate a person's eating, even if that person doesnot suffer from GERD, diurnal GERD, nocturnal GERD, or tLESR. In oneembodiment, the stimulation protocol comprises a plurality of electricalpulses that are continuously applied to the gastrointestinal tract and,more particularly, to an area within 2 cm of the LES. In anotherembodiment, the stimulation protocol comprises a plurality of electricalpulses that are intermittently (and not continuously) applied to thegastrointestinal tract and, more particularly, to an area within 2 cm ofthe LES.

While there has been illustrated and described what is, at present,considered to be a preferred embodiment of the present invention, itwill be understood by those skilled in the art that various changes andmodifications may be made, and equivalents may be substituted forelements thereof without departing from the true scope of the invention.In addition, many modifications may be made to adapt a particularsituation or material to the teachings of the invention withoutdeparting from the central scope thereof. Therefore, it is intended thatthis invention not be limited to the particular embodiment disclosed asthe best mode contemplated for carrying out the invention, but that theinvention will include all embodiments falling within the scope of theappended claims.

We claim:
 1. A system for treating a patient with gastroesophagealreflux disease, comprising: at least one electrode positioned within 3cm above and 3 cm below the patient's lower esophageal sphincter (LES);a waveform generator operably coupled to said at least one electrode; acontroller configured to electrically stimulate the LES to increase thepressure or function of the LES from a first level to a second level,wherein said increase in LES pressure or function above the first leveloccurs during stimulation and continues after stimulation ceases andwherein said controller controls the waveform generator to repeatedly:a) generate and apply an electrical pulse train to the LES through theat least one electrode for a stimulation period, and b) terminate theelectrical pulse train for a rest period.
 2. The system of claim 1wherein said second level is a pressure or function level that reducesat least one of a frequency or duration of occurrence or an intensity ofacid reflux symptoms in the patient.
 3. The system of claim 1 whereinthe electrical pulse train is between 3 mA to 8 mA.
 4. The system ofclaim 1 wherein the stimulation period is between 5 to 60 minutes inlength.
 5. The system of claim 1 wherein the controller is programmed togenerate and apply an electrical pulse train to the LES for 4 to 24stimulation periods per day, wherein each stimulation period isseparated by a rest period.
 6. The system of claim 1 wherein thecontroller is programmed to generate an on period of 0.1 seconds to 60seconds and an off period of 0.1 seconds to 60 seconds within a cycleperiod of 24 hours or more.
 7. The system of claim 1 wherein theelectrical pulse train consists of pulses with frequencies between 10 Hzand 200 Hz.
 8. The system of claim 1 wherein the electrical pulse trainconsists of pulse widths ranging from 100 to 1000 μsec.
 9. The system ofclaim 1 wherein the controller is programmed to generate and apply anelectrical pulse train to the LES for more than 11 stimulation periodsper day, wherein each stimulation period is separated by a rest periodand wherein each stimulation period consists of electrical pulses thatare less than 3 mA.
 10. The system of claim 1 wherein the stimulationperiod consists of electrical pulses that are less than 3 mA beingapplied for a period of time longer than 10 minutes.
 11. The system ofclaim 1 further comprising an accelerometer coupled to the controllerfor sensing posture data of the patient, wherein said controller isconfigured to control the waveform generator to adjust parameters of theelectrical pulse train applied to the LES based on an analysis of saidposture data from said accelerometer.
 12. The system of claim 11 whereinthe controller is configured to switch from a first stimulation mode toa second stimulation mode when said posture data crosses a predeterminedthreshold value.
 13. The system of claim 12 wherein said posture datacomprises time spent in a supine position and said threshold value isset to 1, 5, 30, or 60 minutes.
 14. The system of claim 12 wherein saidposture data comprises level of inclination to a horizontal position andsaid threshold value is set to 140, 150, 160, or 170 degrees.
 15. Thesystem of claim 12 wherein said first stimulation mode comprises a dosemode which provides a pre-programmed stimulation session per time of dayand said second stimulation mode comprises a cyclic mode which providesa stimulation session regularly spaced over a given period of time. 16.The system of claim 12 wherein the controller is configured to apply ablock time after entering said second stimulation mode, wherein nofurther stimulations are applied during said block time and wherein anystimulation begun before entering said second stimulation mode isallowed to complete before initiating said block time.
 17. The system ofclaim 11 wherein the controller is configured to switch from a secondstimulation mode to a first stimulation mode when said posture datacrosses a predetermined threshold value.
 18. The system of claim 17wherein the controller is configured to apply a block time afterentering said first stimulation mode, wherein no further stimulationsare applied during said block time and wherein any stimulation begunbefore entering said first stimulation mode is allowed to completebefore initiating said block time.
 19. The system of claim 1 furthercomprising an impedance sensor coupled to the controller for sensingimpedance values in the LES, wherein said controller is configured tocontrol the waveform generator to adjust parameters of the electricalpulse train applied to the LES based on said impedance values from saidsensor.
 20. The system of claim 19 wherein the system senses andanalyzes said impedance values by recording more than two impedancemeasurements in succession prior to each stimulation session, discardingthe high and low measurement values, checking for inappropriate values,and averaging the remaining values to modify stimulation parametersbased on said average.